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The uses of radiotracers in the life sciences
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2009 Rep. Prog. Phys. 72 016701
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IOP PUBLISHING
REPORTS ON PROGRESS IN PHYSICS
Rep. Prog. Phys. 72 (2009) 016701 (23pp)
doi:10.1088/0034-4885/72/1/016701
The uses of radiotracers in the life sciences
Thomas J Ruth
TRIUMF, Vancouver, Canada
Received 1 August 2007, in final form 27 October 2008
Published 16 December 2008
Online at stacks.iop.org/RoPP/72/016701
Abstract
Radionuclides have been used to follow physical, chemical and biological processes almost
from the time of their discovery. Probably the application with the biggest impact has been in
the medical field where radionuclides have been incorporated into biologically active
molecules and used to diagnose a wide variety of diseases and to treat many disorders. Other
uses in the life sciences, in general, are related to using a radioactive isotope as marker for an
existing species such as nitrogen-13 in plant studies or copper-67 to track copper catalysts in
phytoplankton.
This review describes in general terms these uses as well as providing the reader with the
background related to the physical properties of radioactive decay, the concepts associated
with the production of radionuclides using reactors or accelerators and the fundamentals of
imaging radioactivity. The advances in imaging technology in recent years has had a profound
impact on the use of radionuclides in positron emission tomography and the coupling of other
imaging modalities to provide very precise insights into human disease.
The variety of uses for radiotracers in science is almost boundless dependent only upon
ones imagination.
(Some figures in this article are in colour only in the electronic version)
This article was invited by Professor G Gillies.
Contents
1. Introduction
2. Radioisotope/radionuclide production
2.1. Specific activity
2.2. Reactors
2.3. Cyclotrons
2.4. Generators
3. Radioactive tracers
4. Medical applications
4.1. Historical background
4.2. Radioimmunoassay
4.3. Radiotracers in medicine—ex vivo applications
4.4. Imaging
4.5. Radionuclides for therapy
5. Radiopharmaceuticals
6. Environmental/biological applications
6.1. Agricultural applications
6.2. Plant physiology
6.3. Earth and ocean sciences
6.4. Insect control
6.5. Water resources
7. Concluding remarks
Acknowledgments
References
1
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powering common household items, to producing electricity
for one of every five US homes and businesses.
The first practical application of a radioisotope was made
by George de Hevesy in 1911. At the time, de Hevesy
was a young Hungarian student working in Manchester with
naturally radioactive materials. Not having much money he
lived in a boarding house and took his meals there with his
fellow boarders. He began to suspect that some of the meals
1. Introduction
Just as early man harnessed fire to improve his life, society
in the last century was able to harness radiation. The
development of nuclear technology is one of the most
significant achievements of the 20th century. Today nuclear
technology is used in nearly every field and aspect of our
lives—from medicine, to manufacturing and construction, to
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Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
might be made from leftovers from the preceding days or
even weeks, but he could never be sure. To try and confirm
his suspicions de Hevesy put a small amount of radioactive
material into the remains of a meal. Several days later when the
same dish was served again he used a simple radiation detection
instrument—a gold leaf electroscope—to check whether the
food was radioactive. It was, and de Hevesy’s suspicions
were confirmed. This anecdotal story illustrates the inquisitive
approach de Hevesy took in solving a personal dilemma
while in fact he was heavily involved in his research using
radioactivity to trace lead (Levi 1976).
The use of radionuclides in the physical and biological
sciences can be considered tracer science with special
application to medicine where they are used for imaging and
radiotherapy. Imaging can be further subdivided into planar
imaging, positron emission tomography (PET) and single
photon emission computed tomography (SPECT). All of these
uses rely on the fact that the radionuclides are used at very
low concentration. In order to be used in this manner the
radionuclides and the compounds to which they are attached
must obey the three tracer principles. These state that
140 keV). In addition, the ease with which an iodine atom
can be inserted into a compound makes 123 I extremely
versatile as a radiotracer in SPECT (Lambrecht et al 1972,
Kulkarni 1991, Kung et al 2003).
Rhenium-186 is a β − emitter with a low abundant
γ -ray with an energy of 137 keV. The 1 MeV (maximum
energy) β − -rays and its 90 h half-life make it a
promising radiotoxic nuclide for therapy.
As an
analog of technetium, rhenium possesses similar chemical
properties and can thus be used to label some of the
same compounds that have been previously developed for
imaging tumors (Maxon et al 1990, Kolesnikov-Gauthier
et al 2000).
Most of the radiotracers have relatively short half-lives
(from less than a few hours to at most a few days). There
are definite advantages in using short-lived radionuclides. For
example, there is a low radiation dose associated with each
study, serial studies are possible (sometimes on the same day
for tracers such as 11 C) and the radioactive waste disposal
problems are minimized if not eliminated. The disadvantages
include the need for an accelerator or other source nearby
or within easy shipping distance for the longer lived species
and rapid chemical procedures, especially for more complex
compound formation.
Throughout the rest of this paper, examples of the
application of radioactive tracers will be provided in some
detail and the high sensitivity of the techniques will be
illustrated.
• the tracer behaves or interacts with the system to be probed
in a known, reproducible fashion,
• the tracer does not alter or perturb the system in any
measurable fashion and
• the tracer concentration can be measured.
In radiotherapy, the second principle is, in a strict sense,
broken since the point of delivering the radiotoxic substance is
to have the emitted radiation cause damage to the undesirable
surrounding tissues. However, in order for the radiotoxic
substance to localize in sufficient quantities it must follow
the known chemical behavior without perturbing that pathway,
and thus behave like a tracer. When radiotracers are used for
diagnostic or therapeutic purposes, imaging and radiotherapy,
respectively, they are referred to as radiopharmaceuticals
since they must be of pharmaceutical quality for human use.
Radiopharmaceuticals will be discussed further later.
The following are some typical radionuclides used in each
of the broad categories.
2. Radioisotope/radionuclide production
Radionuclide production is indeed true alchemy, that is,
converting the atoms of one element into those of another.
This conversion involves altering the number of protons and/or
neutrons in the nucleus (target). If a neutron is added without
the emission of proton(s) then the resulting nuclide will have
the same chemical properties as the target nuclide—differing
only in mass. If, however, the target nucleus is bombarded
by a charged particle, for example, a proton, the resulting
nucleus will usually be that of a different element. The exact
type of nuclear reactions that a target undergoes depends on
the number of parameters including the type of bombarding
particle and the energy of this projectile.
The binding energy per nucleon in the nucleus is on the
order of 8 MeV. Therefore, if the incoming projectile has more
than this amount of energy, the resulting reaction will cause
other particles to be ejected from the target nucleus. By
carefully selecting the target nucleus, the bombarding particle
and its energy, it is possible to produce a specific radionuclide.
Figure 1 illustrates the various exit routes from the production
of the compound nucleus generated by bombarding nitrogen14 with protons.
A more complete description of the process of
radionuclide production is given below.
Carbon-11 is a positron emitting radionuclide with a halflife of 20.3 min. It is generally produced as 11 CO2 which
can be converted into a wide variety of labeling agents
such as 11 CH3 I or H11 CN. Since carbon is a constituent
of all biological compounds, 11 C finds widespread use as
a tracer in PET. In fact, more than 200 compounds have
been labeled with C-11 (Iwata 2002).
Nitrogen-13 is also a positron emitting radionuclide.
However, in addition to its use as a cardiac blood flow
agent (in the form of 13 NH+4 ) it is used in applications
other than PET imaging. For example, it is widely used in
botany studies to determine the kinetics of nitrogen uptake
in a variety of plant systems under a variety of conditions
(Bingham 2000, Glass 2002). Detailed examples will be
discussed in section 6.
Iodine-123 emits γ -rays with an energy of 159 keV. This
is ideally suited for imaging in SPECT cameras, as they
have been optimized for use with 99m Tc (γ -ray energy =
2
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
99
235
U
Mo
236
U
Neutron
135
Figure 1. Schematic illustration of the possible nuclear reactions
from the bombardment of N-14 with protons. The relative amounts
of each of the product nuclei will depend upon the energy of the
incoming proton.
Figure 2. Schematic of the fission process following neutron
capture by U-235. The unstable compound nucleus breaks into 2
fragments with a distribution as shown in figure 3. Between 2 and 3
neutrons accompany the breakup of the compound nucleus.
2.1. Specific activity
9.3 × 109 Ci mol−1 . In SI units we have 340 exabecquerels per
mole (3.4 × 1020 Bq mol−1 ).
If the substance had instead been 14 C-labeled with its
5715 y half-life, then following the same process, but using
the decay constant (λ = 3.84 × 10−12 s−1 ) for 14 C, the
resulting specific activity would be 6.2 × 104 mCi mol−1 or
62 CIF mol−1 . If the radiolabeled glucose had been prepared
in a growing plant, the naturally occurring glucose would have
lowered the SA due to the non-radioactive glucose molecules.
Therefore, it is easy to see that short-lived radioisotopes have
the potential for much higher specific activity but this also
depends upon the chemical purity.
Specific activity is a measure of the number of radioactive
atoms or molecules as compared with the total number of those
atoms or molecules present in the sample. The specific activity
is usually expressed in terms of radiation units per mass unit.
The traditional units have been Ci mol−1 (Ci g−1 ) or a fraction
thereof (now expressed in SI units as GBq mol−1 ). If there
are no stable or radioactive contaminants of the same element,
then the sample is referred to as carrier free. For example,
a compound labeled with 211 At will be carrier free since there
are no stable isotopes of astatine (assuming, of course, that
there are no other radioisotopes of astatine present).
However, in most cases there are small quantities of
unlabeled compounds that have a similar chemical behavior
and can act as pseudo-carrier. By pseudo-carrier it is meant
that while there may not be true isotopic species present, the
molecules co-existing with the compound in question possess
similar chemical behavior and thus represents a contamination.
The specific activity of an isotope or radiopharmaceutical is
important in determining the chemical/biological effect the
substance may have on the system under investigation.
The number of radioactive atoms, N , in a sample can be
calculated from the relationship of radioactivity to quantity of
material present and expressed as
dN/dt = −λN,
Sn
2.2. Reactors
Following the Second World War reactors began to be used for
a number of research areas including radionuclide production.
The use of nuclear reactors for the production of radionuclides
relies on the fact that during the fission process in a reactor,
there are large numbers of neutrons produced with a wide
range of energies. These neutrons can be used directly or
thermalized (slowed) by the surrounding media. The term
thermal neutron means they have kinetic energy associated
with room temperature (about 0.025 eV). These thermalized
neutrons are ideal for initiating (n,γ ) reactions. In some
reactors, higher energy or fast neutrons (>1 MeV) are used to
produce radioisotopes via other reactions, for example, (n,p)
or (n,α) reactions. Figure 2 illustrates the fission process.
The fission process is a source of a number of widely
used radionuclides. For example, 90 Sr, 99 Mo, 131 I and 133 Xe
are all produced in reactors by fission and can be separated
from uranium fuel cells or from targets of enriched 235 U
placed in the reactor for radionuclide production directly.
The distribution of isotopes (both radioactive and stable) is
illustrated in figure 3. The peak of the lower mass is at mass
99 which includes Mo-99. Approximately 6% of all fissions
yield Mo-99; thus the fission approach is a very efficient mode
of production for this important radionuclide.
The major drawbacks from using fission produced
materials are the large quantities of radioactive waste material
generated and the large amounts of radionuclides produced
(1)
where dN/dt is the disintegration rate per second, while λ is
the decay constant in reciprocal seconds (λ = ln(2)/t1/2 ).
As an example of specific activity assume that glucose has
been labeled with 10 mCi of C-11 with a half-life of 20.3 min.
Its carrier free specific activity would be obtained by first
determining the number of 11 C atoms:
− dN
(10 mCi)(3.7 × 107 dps mCi−1 )
N11 C = dt =
ln(2)
λ
(20.3 min)(60 s min−1 )
= 6.5 × 1011 atoms.
Using Avogadro’s number, the number of moles is then
1.08 × 10−12 . Dividing the amount of radioactivity by the
number of moles we have 9.3 × 1012 mCi mol−1 or a SA =
3
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
Table 1. The most commonly used positron emitters and typical
reactions for their production.
Radionuclide
t1/2
Decay
mode
11
13
C
N
20.3 min
9.97 min
β+
β+
15
O
2.03 min
β+
18
F
110 min
β+
a
Reaction
14
N(p,α)
O(p,α)
13
C(p,n)a
15
N(p,n)a
14
N(d,2n)
16
O(p,pn)
18
O(p,n)a
nat
Ne(d,α)
16
Energy
(MeV)
11–17
19
11
11
6
>26
11–17
8–14
These reactions required enriched target material.
disrupt the neutron flux. Typically only longer lived (>1 d)
radionuclides are produced in reactors. In addition, as very
few new reactors are being built, the availability of this
source of radionuclides for medical and scientific endeavors
is diminishing1 .
2.3. Cyclotrons
It is ironic that the first artificially produced radionuclides
were created on Lawrence’s cyclotrons (Lawrence and
Livingston 1932, Lawrence 1940), but it took another 30
years before accelerator produced radionuclides began to
play a major role in the production of medically important
radiopharmaceuticals. The principal advantage of accelerator
produced radionuclides is the high specific activities that can
be obtained through the (p,xn) and (p,α) reactions that result
in the product being a different element from the target.
Another significant advantage is that a smaller amount of
radioactive waste is generated from charged particle reactions
in comparison with reactor production.
Cyclotrons used for producing medical radionuclides were
initially designed for physics experiments and used only part
time for medical applications. These cyclotrons were capable
of accelerating protons, deuterons, 3 He+2 and α-particles (the
nucleus of 4 He). As can be seen from table 1 however,
the PET radionuclides are produced from either proton or
deuteron reactions. In the early 1980s, small compact protononly cyclotrons became available and cyclotrons specifically
designed for producing PET radionuclides were installed in a
few hospitals.
The principle of the cyclotron is based on the application
of small accelerating voltages repeatedly. Figure 4 shows the
principal components of a cyclotron. Hollow cavities called
dees because of their shape serve as the electrodes for the
acceleration. A radiofrequency (RF) oscillator is connected
to the dees such that the electrical potential on the dees is
alternatively positive and negative with respect to each other.
By placing the dees between the poles of a strong magnet so
that the magnet field is perpendicular to the plane of motion,
the charged particle undergoing acceleration will move in a
circular path. As the particle gains energy it moves in a
Figure 3. The two curves show the asymmetric yield distribution of
radioisotopes as a function of atomic mass from the fission of U-235
(solid curve) and from Pu-239 (dashed curve). Note that the yield
peaks on the lower mass hump at mass equal to 99. This is why
reactor production of Mo-99 is so favorable (C C Lin,
Radiochemistry in Nuclear Power Reactors, National Academy
Press (1996)).
including isotopes of the desired species. The co-produced
radionuclides become a radioactive waste issue if other uses
cannot be identified. In producing 131 I from fission, the
isotopes 127 I and 129 I are also formed, thus reducing the specific
activity. Since 131 I is obtained from the decay of 131 Te, neutron
capture on enriched 130 Te is utilized to produce the required
131
Te. As such, the isotopic purity of the 131 I is directly related
to the level of enrichment of the target material, 130 Te. 131 I
is then extracted from the tellurium oxide via dry distillation
at around 600–650 ◦ C. This is an analogous approach to that
which is used to extract 123,124 I from cyclotron irradiated targets
of 124 Te.
Because 235 U enrichment above 20% constitutes weapons
grade material (typically the enrichment is as high as 93%
235
U), there is growing concern regarding its use for the
production of medical radionuclides.
While there are
processes in place for the use of lower enrichment (which
means dealing with larger waste streams) the major producers
have not switched over as of 2008.
Reactor production offers some advantages in that
production is carried out in a passive mode. That is, in the
presence of neutrons, the targets are inserted and withdrawn
throughout an operational cycle. Insertions and withdrawals
are performed under controlled conditions, so as to not greatly
1 For further reading see IAEA TECDOC 1340 ‘Manual for Reactor Produced
Radioisotopes’.
4
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
(3)
vacuum tank, magnet, ion source, extraction system) there have
been some innovations in the last few decades that have had a
major impact on the design of the modern cyclotron. The two
most significant changes have occurred in getting the ions into
the cyclotron (ion source) and out of the cyclotron (extraction
system).
Nearly all modern cyclotrons now use a negative ion
source. Ions are generated by passing the source gas through
an electric field that generates negative and positive ions (e.g.
in the case of H2 , the resulting ions will be H+ or protons and
H− ions, a proton with 2 electrons). The advantage of negative
ions resides in the ability to easily have a variable energy
cyclotron, to have nearly 100% extraction (see below) and to be
able to extract multiple beams, simultaneously. The design of
the ion source has also changed in that the ion source can reside
inside the cyclotron where the ions are generated at the center of
the cyclotron (central region) or from outside of the cyclotron
(external ion source) and subsequently injected into the central
region for acceleration. There are obviously advantages and
disadvantages to each approach. With an external ion source
the vacuum can be operated at very low pressures with very
little beam loss due to stripping of the negative ion by the
residual gas. However, the vacuum system must be of a very
clean nature to maintain this high vacuum. With an external
ion source, maintenance can be performed without opening the
cyclotron or breaking vacuum. In addition the central region
is not disturbed as in the case of the internal ion source that is
part of the central region.
The simplicity of the design for proton-only cyclotrons
resulted in cyclotrons which accelerate H− ions capable of
two or more simultaneous beams of varying energies and
intensities. The modern cyclotron is completely controlled
by a computer and is capable of running for many days with
minimal attention. The major drawback from these proton
cyclotrons lies in the fact that in some cases an enriched target
material must be used for a sufficient product to be generated.
One of the major drawbacks to the widespread availability
of PET is the high capital cost associated with the cyclotrons
and scanners. However, the success of the small low energy
cyclotron encouraged research into the design of even lower
energy accelerators, i.e. linear accelerators and cyclotrons of
a few megaelectronvolts extracted energy. To date, there are
very few of these machines in routine use.
Regardless of the type of accelerator used to produce the
radionuclides, the production rates depend on the flux of the
bombarding particles, the number of target nuclei and the
probability of the reaction occurring. The equation for the
rate of production is
R = I σ t,
(4)
where m is the mass of the ion, e is its charge and v its velocity
with B equaling the magnetic field and r is the radius of the
ion’s orbit. Thus the orbit of the particle is directly proportional
to the particle momentum and the particle orbit frequency is
constant and independent of energy. This principle breaks
down under relativistic effects where the mass is not constant.
While the basic components of modern cyclotrons are
essentially the same as the original designs (RF cavities,
where R is the rate of nuclei formed per second, I is the flux of
the bombarding particles per second, σ is the cross section
(probability of the reaction occurring) in cm2 and t is the
target thickness expressed as the number of nuclei per square
centimeter. It is of historical interest to note that the unit for
cross section is the barn, which is equivalent to 10−24 cm2 . The
expression ‘barn’ comes from the fact that the probability of a
neutron interacting with a target is proportional to the area of
Figure 4. Photograph of the interior of a cyclotron shows the copper
‘dees’, the accelerating component of a cyclotron and the 4 ‘hills’ of
the steel magnet. This cavity is enclosed with a plate so that a
chamber capable of sustaining a vacuum is formed. Ions of a light
particle such as hydrogen or helium are injected into the center of
the cyclotron where they are accelerated by the electrically charged
dees. The dees are high voltage cavities that change polarity
(electrical charge) at a high frequency (radiofrequency—tens of
megahertz). The magnet forces the charged particles to move in a
circular path. As the particle gains energy the circular path increases
in radius until it reaches the energy desired whereupon it is extracted
and directed to a target material where a nuclear reaction forms the
radionuclide of choice. (Photo of TRIUMF TR13 cyclotron.)
spiral outward from the center. With the source of negative
ions at a point in the center of the cyclotron the positive dee
will accelerate the ions toward that dee with the magnetic
field forcing them to move in a curved path. Once inside
the cavity the particles no longer experience an electric force.
Continuing in the circular path the particles will exit the dee
and enter the gap between the dees where the second dee has
changed its potential to be an attracting force, accelerating the
particles to that dee. The dees reverse their potential when
the particles are inside the dees so that at each crossing of the
gap the particles receive an increase in energy of the order of
20–50 keV. Lawrence discovered the equations defining this
principle of operation in 1929 and built the first cyclotron in
1931.
Bev = mv 2 /r
and
r = mv /Be.
(2)
Since angular velocity ω = v /r, then
ω = Be/m,
5
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
the nucleus, which, compared with the size of the neutron, is
as big as a barn.
The rate of production is, of course, affected by the fact
that the resulting nuclide is radioactive and thus undergoes
radioactive decay. For short-lived nuclides the competing
reaction rates, production and decay will achieve equilibrium
at sufficiently long bombardment times since the rate of decay
is proportional to the number of radionuclei present. The
point where equilibrium is reached is called saturation. This
means that there is no benefit to longer irradiations, as the
production rate equals the rate of decay, and therefore no
additional product will be formed. At shorter irradiation times
the fraction of product produced is related to the saturation
factor given by (1 − e−λt ), where λ is the decay constant of the
decaying nuclide and t is the bombardment time. It is evident
that an irradiation equivalent to one half-life would result in a
saturation factor of 50%. For practical reasons, an irradiation
rarely exceeds three half-lives (90% saturation) except for the
shortest-lived radionuclides.
For long lived species, the quantity produced is usually
expressed in terms of the integrated dose or the total beam flux
(µA h). For example, with a long lived radionuclide such as
82
Sr (t1/2 = 25 d) the amount produced will be essentially the
same whether it is produced from 100 µA in 1 h or 50 µA in
2 h (both represent 100 µA h of the beam)2 .
λd , and the number of radioactive nuclei, N , present (λd N ).
The first term accounts for the growth of the daughter as a
function of the decay of the parent as well as the disappearance
of the daughter due to its own decay. The last term accounts
for the presence of daughter nuclei at zero time.
All generator systems used routinely in nuclear medicine
form an equilibrium between parent and daughter radionuclei.
In the case of the 99 Mo/99m Tc generator, the parent (99 Mo)
decays at a rate relatively similar to that of the daughter (99m Tc).
With a half-life of 66 h for 99 Mo versus 6 h for 99m Tc, there is
an appreciable decay of the parent before the daughter reaches
steady state. This steady state condition is referred to as
transient equilibrium. With transient equilibrium, the daughter
radioactivity grows in and surpasses that of the parent before
equilibrium is reached. The ratio of the daughter radioactivity
to that of the parent is given by equation (6),
Tp
Ad
=
,
Ap
Tp − T d
(6)
where T is the half-life for each species, respectively (see
figure 5).
The useful lifetime of the 99 Mo/99m Tc generator is
determined by two factors: (1) the amount of 99m Tc that
can be eluted from the generator in a volume suitable for
use in the diagnostic procedure and (2) the amount of 99 Mo
that is co-eluted or the amount of breakthrough. The US
Pharmacopeia and the US Nuclear Regulatory Commission
or equivalent Agreement State regulations specify a limit of
0.00015 MBq molybdenum Mo-99 per MBq of technetium
Tc-99m (0.15 µCi Mo-99/mCi Tc-99m) at the time of
administration to each patient.
For the situation where the parent has a half-life much
longer than the daughter, e.g. 68 Ge/68 Ga and 82 Sr/82 Rb, the
change in the amount of the parent during the time for steady
state to be reached will be negligible; the steady state condition
is referred to as secular equilibrium. The quantity of daughter
activity at any time is then expressed by equation (7)
2.4. Generators
Finally, the other source of radionuclides used in medicine
is the generator. The most widely used generator system is
the 99 Mo/99m Tc pair, where over 80% of all nuclear medicine
procedures performed worldwide use Tc-99m as the imaging
radionuclide. There are numerous Tc-99m kits for producing
tracers to examine the brain, kidney, heart, bone, liver, lung,
red blood cells and TcO−
4 for thyroid. The parent Mo-99 is
produced in a reactor, usually as a fission product from U-235.
A radioactive generator takes advantage of the cases
where one longer lived (parent) radionuclide decays, usually
by β − emission, to a shorter lived (daughter) radionuclide.
The chemical differences in the two elements are exploited to
separate the daughter product from the parent. The parent
radionuclide is produced by one of the methods described
above and then attached to an inert substance from which the
desired product can be eluted or washed off the support. The
product can be used directly as in the case of 82 Rb+ from the
Sr/Rb generator or after undergoing a chemical reaction in the
case of 99m Tc from the Mo/Tc generator (see below).
The equilibrium equations that reflect the relative
radioactivity of parent and daughter are given by the general
equation:
(λd )(e−λp t − e−λd t )
Ad (t) = Ap (0)
+ Ad (0)e−λd t , (5)
λd − λ p
Ad (t) = Ap (0)(1 − e−λd t ).
(7)
Thus, in secular equilibrium, when e−λdt ≈ 0, the daughter
and parent radioactivity are approximately equal.
From table 2, it is easy to see that generators have a
wide variety of uses and half-lives of both parent and daughter
nuclides. Obviously, from an end user perspective, the long
lived parent makes it possible to have a single generator in use
for an extended period of time. The utility of the generator is
actually based primarily on the daughter’s half-life and the
chemistry required to provide the radionuclide in a useful
species. The simplest systems make use of the daughter
nuclide directly; 82 Rb+ and 81m Kr are used directly as a K+
ion analog and as an inert gas ventilation tracer, respectively.
3. Radioactive tracers
where A is the radioactivity of the daughter ‘d’ and parent ‘p’,
respectively. Ad is equal to the product of the decay constant,
In addition to the use of radionuclides in medicine there are
a wide variety of uses for following the behavior of system,
both on the large scale such as the environment and a much
2
For further reading see IAEA TecDoc ‘Theory and Practice of Production
of Radioisotopes Using Cyclotrons’ 2007 (at press).
6
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
Table 2. Examples of generator systems available today.
99
68
Mo/99m Tc
68
Parent
t1/2
Daughter
t1/2
66 h
6h
Ge/ Ga
270 d
68 m
Sr/82 Rb
188
W/188 Re
25.5 d
69 d
76.4 s
16.9 h
81
225
Rb/ Kr
Ac/213 Bi
4.58 h
10.0 d
13 s
45.6 m
62
Zn/62 Cu
9.26 h
9.7 m
82
81m
Uses
9
Tc-99m is the most
widely used radionuclide
in nuclear medicine,
single photon emitter
In equilibrium as a long
lived positron source;
Ga metal chemistry
Cardiac blood flow
Radionuclide therapy
(β-particles)
Lung ventilation studies
Radionuclide therapy
(α-particles)
Blood flow, hypoxia
8
Mo-99
Tc-99m
7
Curies
Generator
Activity versus Time, Mo-99 and Tc-99m
10
6
5
4
3
2
1
0
0
24
48
72
96
120 144 168 192 216 240
Hours
Figure 5. Illustration of the decay of Mo-99 with the in-growth of
Tc-99m.
smaller scale as in the chemical process in the lab. As
indicated in the introduction the term radiotracer refers to a
radioactive species that is used to follow (trace) the uptake
into or function of an organ system in a living plant, animal
or physical/chemical process. Initially, the radiotracers used
were radioactive isotopes of naturally occurring elements
as in the case where de Hevesy used radioactivity to trace
food leftovers in his boarding house (see above). While
early radiotracer applications used simple, naturally occurring
elements, today the use of radiotracers is based on the
production of radionuclides by one of the aforementioned
methods.
Radioactive isotopes of the elements of sodium and
potassium (24 Na, 42 K) have been used as chloride salts to
measure the sodium and potassium content of the body
employing the isotope dilution technique. Analysis by isotope
dilution involves the addition of a known mass and specific
activity of a particular isotope to a mixture containing an
unknown quantity of that element. An aliquot of the mixture
is then analyzed to determine the new specific activity of the
substance under investigation. It can be shown that the mass,
M, of the substance of interest in the unknown mixture may
be expressed as
S1
−1 ,
(8)
M = M1
S2
4. Medical applications
Nuclear medicine makes use of the fact that certain
radionuclides emit gamma rays with sufficient energy for
detection outside of the body. In attaching such radionuclides
to biologically active compounds, the activity will either
localize within particular bodily tissues or be free to
follow a particular biochemical pathway. The radiotracers
that are used to study bodily function are referred to as
radiopharmaceuticals. The term has been used because of
the similar properties between these tracers and the drugs or
pharmaceuticals that have been developed to treat disease. The
following discussion will concentrate on the uses of radioactive
substances for the diagnosis of human pathology using imaging
as well as by taking samples from blood or exhaled air and in
their use for therapeutic treatment.
4.1. Historical background
Nuclear medicine (NM) has its origins in the pioneering work
of the Hungarian doctor, G de Hevesy, who, in 1924, used
radioactive isotopes of lead as tracers in bone studies. These
studies were in addition to his amateur detective work at his
boarding house. Shortly thereafter, Stevens made intravenous
injections of radium chloride to study malignant lymphomas
(1926).
However, it was not until the discovery of artificially
produced radioactive isotopes that the number of available
species suitable for use as tracers began to increase. The
invention of the cyclotron by Ernest Lawrence in 1932 made
it possible to produce radioactive isotopes of a number of
biologically important elements. The use of these artificially
produced radiotracers continued with J G Hamilton and
R Stone using radioactive sodium clinically in 1937. S Hertz,
A Roberts and R D Evans, in 1938, used radioactive iodine
in the study of thyroid physiology, followed, in 1939, by
J H Lawrence, K G Scott and L W Tuttle in the study of
leukemia with radioactive phosphorus. By 1940 J G Hamilton
and M H Soley were performing studies in iodine metabolism
where S1 and S2 are the specific activities of the tracer added
before and after addition to the system, respectively, and M1
is the mass of the spike added to the system.
As an example, suppose the amount of copper in a system
was to be determined. A spike of copper containing 0.5 mg
with 5 kBq of 64 Cu is added to 20 mL of the unknown sample.
After addition and mixing, a portion of the mixture is isolated
and the specific activity (Bq mg−1 ) of copper is determined.
In this example, say that the analysis yields a S2 value of
0.024 kBq mg−1 . Using the above equation the amount of
copper in the unknown sample is
M = 0.5 mg × ((10 kBq mg−1 /0.024 kBq mg−1 ) − 1)
= 207 mg of copper.
This method of isotope dilution has a number of applications,
especially in tracer elemental analyses of living systems.
7
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
by the thyroid gland in situ by comparing the use of radioiodine
in control subjects to patients with various types of goiters
(Harbert and da Roche 1984).
The first medical cyclotron was installed in 1941 at
Washington University, St Louis, where radioactive isotopes
of phosphorus, iron, arsenic and sulfur were produced. With
the development of the fission process during the Second
World War (WWII), most radionuclides of medical interest
began to be produced in nuclear reactors. After WWII the
wide use of radioactive materials in medicine established a
new field of what was then called atomic medicine and only
later became known as nuclear medicine. Radioactive carbon,
tritium, iodine, iron and chromium found increasing use in the
study of disease processes.
Ben Cassen, 1951, developed the concept of the rectilinear
scanner which opened the way to obtaining the distribution of
radioactivity in a subject within a short time. This was followed
by the production of the first gamma camera by Hal Anger in
1958. The original design was modified shortly afterwards
to what is now known as the Anger scintillation camera, thus
heralding the modern era of gamma cameras whose principles
are still in use today.
Powell Richards developed the 99 Mo/99m Tc generator
system at the Brookhaven National Laboratory in 1957.
Technetium-99m produced via this generator system has
become the most widely used radionuclide in nuclear medicine
today accounting for as much as 80% of all diagnostic
procedures (see table 3 for a list of radiopharmaceuticals).
The modern era of nuclear medicine has become known
as molecular medicine, as the field translates advances in
molecular biology and biochemistry into the treatment of
human disease and the diagnosis of pathology and anatomical
abnormalities. The advent of clinical PET for cancer diagnosis
makes use of sophisticated tracers to unravel cancer biology.
for the unknown and the standards to be chemically identical or
to have identical biological behavior. The original technique
has been modified by making use of a variety of radiotracers to
measure concentrations of vitamins, enzymes, peptides, serum
proteins, hormones, viruses, drugs and tumor antigens (Ruth
1994).
Commercially available kits provide the materials for
performing RIA. A typical kit would consist of a series of
standard samples each containing a specific amount of an
unlabeled antigen, a vial of a labeled antigen, a vial of
antibody and a substance used to precipitate the antigen–
antibody complex. In most cases I-125 is the isotope employed
as the radioactive label on the antigen.
4.3. Radiotracers in medicine—ex vivo applications
In the development of drugs or even biomarkers the use of
radiotracers labeled with 3 H and 14 C have played an important
part in determining the biodistribution as a function of time
after injection and the determination of the pharmacokinetics
of the substances under investigation. These studies involve the
administration of the tracer to a rodent (rat or mouse) and the
sacrificing of the animal at specific time points with the organ of
interest excised for further analysis. The analysis may involve
preparing slices of the organ and placing the slices on film
or on phosphorimaging devices so that autoradioradiographic
images can be prepared. High resolution images are possible
due to the short range of the beta rays from the decay of 3 H and
14
C. Phosphorimagers use a film embedded with light sensitive
crystal that absorbs the energy of decay of the radioactive
substance to form an excited electronic state in the crystals of
the film and the image is read by excitation with a laser digitally
stored on a computer. With traditional autoradiography, an
x-ray film is exposed to the radioactive substance and the film
is developed to provide the image. The advantage of the
phosphorimager is that the film can be reused by exposing
the film to white light to return the crystals to the unexcited
state.
Small animal imaging (SPECT and PET) is an attempt
to duplicate this technique, however performed in vivo as
discussed below.
4.2. Radioimmunoassay
Based on the radioisotope techniques developed in the early
1950s S Berson and R Yalow published in 1959 the first use
of radioimmunoassay (RIA) to measure the concentration of
insulin in an unextracted human plasma. The RIA principle is
simple and is illustrated by the schematic in figure 6.
The concentration of an unknown amount of unlabeled
antigen can be determined by comparing its inhibitory effect
on the binding of radioactively labeled antigen to a specific
antibody with the inhibitory effect of known standards (Yalow
1978). The use of radioactive tracers makes the method
sufficiently sensitive for detecting very small quantities. For
example, in some species, concentrations of less than 1
picomolar can be determined. The technique involves the
separation of the labeled antigen of interest into bound and
unbound fractions after interaction with an antibody in the
presence of an unknown amount of unlabeled antigen. The
ratios of the bound to free fractions of the labeled antigen are
compared with the binding of known standards.
The method of measurement requires only that the antigen
in test samples and the antigen in standard samples have
identical immunologic behavior. Therefore, it is not necessary
4.4. Imaging
Nuclear medicine imaging differs from other radiological
imaging techniques in that the radiotracers used in nuclear
medicine relate to the function of an organ system or metabolic
pathway and thus the tracing of these agents reveals the
integrity of these systems or pathways. This is the basis for
the unique information that a nuclear medicine scan provides.
Planar imaging. By far the most common imaging device in
nuclear medicine is the planar camera or the Anger camera.
The basic components of the camera include a thin crystal of
NaI scintillator coupled to a cluster of photomultiplier tubes
(PMTs), an X, Y positioning circuit and a readout device
that may be an oscilloscope or photographic film. The NaI
scintillator design minimizes multiple interactions with the
incident γ -rays so that the position of interaction can be
8
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
Table 3. Technetium-based radiopharmaceuticals.
Generic name
Product name
Use
Manufacturer
99m
Technetium generator
Ultra-TechneKow FM
Supply of
Tc
Technetium generator
Supply of 99m Tc
TechneLite
Supply of 99m Tc
Aggregated albumin
Macrotec
Lung imaging
TechneScan MAA
Lung imaging
Pulmolite
Lung imaging
Aggregated albumin
Lung imaging
MPI MAA
Lung imaging
Albumin colloid
Microlite
Imaging of RE system
Serum albumin
HSA Kit
Blood pool imaging
Disofenin
Hepatolite
Hepatobiliary imaging
Exametazime
Ceretec
Cerebral perfusion
Lidofenin
TechneScan HIDA
Hepatobiliary imaging
Mebrofenin
Choletec
Hepatobiliary imaging
Medronate
Osteolite
Bone imaging
AN-MDP
Bone imaging
TecheScan MDP
Bone imaging
MDP-Squibb
Bone imaging
Medronate
Bone imaging
TechneScan MDP
Bone imaging
Mertiatide
TechneScan MAG3
Renal imaging
Oxidronate
OsteoSan HDP
Bone imaging
Penetate sodium
DTPA
Kidney and brain imaging
AN-DTPA
Kidney and brain imaging
Techneplex
Kidney and brain imaging
Pyro- and tri- metaphosphates TechneScan PYP
Bone imaging
Phosphotec
Bone imaging
Pyrolite
Bone imaging
AN-Pyrotec
Bone imaging
Red blood cell kit
Ultratag RBC
Bloodpool imaging
RB-SCAN
Blood pool imaging
Sestamibi
Cardiolite
Myocardial imaging
Gluceptate
Glucoscan
Kidney and brain imaging
TechneScan Gluceptate Kidney and brain imaging
Succimer
DMSA
Renal studies
Sulfur colloid
Sulfur Colloid
Gastrointestinal and organ studies
Tesuloid
Gastrointestinal and organ studies
AN-Sulfur Colloid
Gastrointestinal and organ studies
Teboroxime
CardioTec
Myocardial imaging
Source: R Brown, Mallinckrodt, Inc., personal communication, April 6, 1994.
Mallinckrodt
Medi-Physics
DuPont-Merck
Squibb
Mallinckrodt
DuPont-Merck
CIS-US
Merck Sharp & Dohme
Dupont-Merck
Medi-Physics
Dupont-Merck
Amersham
Merck Sharp & Dohme
Squibb
DuPont-Merck
CIS-US
Merck Sharp & Dohme
Squibb
Medi-Physics
CIS-US
Mallinckrodt
Mallinckrodt
Medi-Physics
CIS-US
CIS-US
Mallinckrodt
Squibb
DuPont-Merck
CIS-US
Mallinckrodt
Cadema
DuPont-Merck
DuPont-Merck
Merck Sharp & Dohme
Medi-Physics
Medi-Physics
Squibb
CIS-US
Squibb
Note: The trade names and the names of the producers may have changed in the intervening years. From Adelstein and
Manning (1995).
Labeled antigen
+
Labeled antigen-antibody complex
↔
Ab
Ag*-Ab
+
Ag
Unlabeled antigen in known
standard solutions or unknown samples
↔
Ag*
Specific antibody
Ag-Ab Unlabeled antigen antibody complex
Figure 6. Schematic representation of the reactions used in RIA.
9
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
determined with great accuracy. Typical scintillation cameras
have detectors 25–45 cm in diameter and 0.64–1.27 cm in
thickness.
The X, Y positioning circuit relies on the light output
from the many (19–91) PMTs mounted on the back of the
scintillator. The PMT located nearest to the γ -ray interaction
will receive the maximum amount of light, and the other PMTs
will receive light in proportion to the solid angle subtended by
the tube at the point of interaction. The positioning circuit
sums the output of the PMTs and produces X and Y pulses
proportional to X and Y coordinates of the γ -ray interaction.
In between the radioactive source and the detector is a
collimator constructed of dense metal such as lead or tungsten.
The collimator has one or more holes drilled through it to allow
the passage of γ -rays. Since γ -rays cannot be bent or focused
the collimator’s function is to absorb those γ -rays that do not
pass through the openings.
In its simplest form the collimator has a single pin hole and
acts like a camera lens. Other collimators are constructed with
the holes converging, diverging or parallel to the imaginary line
connecting the object to be imaged and the camera face. The
converging collimator has the effect of magnifying the imaged
object while the diverging collimator magnifies the object. The
parallel collimator is used for high resolution. Regardless of
which collimator is used they all absorb a large fraction of the
photons emitted by the radiotracer in the patient.
γ
ee+
γ
11
B
11
C
Figure 7. Illustration of positron decay. One of the protons (red) in
the unstable nucleus is converted into a neutron (blue) with the
emission of a positive electron (positron) which travels a short
distance until it is annihilated with a neighboring atomic electron
resulting in their annihilation giving 2 photons (γ -rays), each with
an energy of 511 keV. The photons will travel at nearly 180◦ from
each other to conserve momentum.
from 201 Tl having a scatter fraction of as much as 40–50%
depending on the depth of the source. It is for these reasons
that attenuation and scatter exert significant and difficult nonlinear effects that are difficult to correct.
Whereas scintillation camera images show the distribution
of the radiopharmaceutical in defined regions in planar view,
they suffer from the superimposition of organs and background
contributions to the areas of interest. It is because of these
shortcomings in planar imaging that SPECT has a major role
to play in diagnostic imaging regardless of whether SPECT can
achieve the difficult task of providing quantitative information.
The ability to view the distribution in three dimensions greatly
affects the interpretation of the images.
Single photon emission computed tomography. As with
PET, single photon emission computed tomography, SPECT,
acquires views of the emitted photons from many different
angles and re-projects these views to reconstruct an image of
the three-dimensional distribution of radioactivity in the object
or patient. In SPECT, the radiopharmaceuticals used contain
radionuclides such as 99m Tc that emit single photons (ones that
are not in timed coincidence with one another). Directional
information is achieved by collimating the photons incident
on the detector of the Anger camera. The collimator thus
reduces the sensitivity of the camera because all of the photons
not parallel to the holes in the collimator are prevented from
reaching the detector surface.
Since the reconstructed image contains three-dimensional
information on the distribution of radioactivity, SPECT also
has the potential for quantification. The factors effecting this
capability are similar to those in PET, e.g. system sensitivity,
dead-time, spatial resolution, sampling interval, reconstruction
filters and the size of the object being imaged. Also, as in PET,
the photons emerging from the subject are attenuated by the
amount of matter between their origin and the detector, and,
of course, they have a definite probability of being scattered
along their path.
Because of the inherently lower energies (100–150 keV)
of the photons emitted by radionuclides used in SPECT, the
effect of attenuation can be quite dramatic with reductions
as great as a factor of 5 or more. Thus, with single photon
emitters, it is difficult to determine whether data reflect a weak
source near the surface or a stronger source located at some
greater depth. In addition, the amount of scatter is strongly
dependent on the energy of the photons, with the photons
Positron emission tomography. PET imaging makes use of
the self-collimating nature of positron decay (see figure 7), as
two nearly collinear photons are utilized to define the location
of an annihilation event. PET cameras are typically made of a
ring of detectors that are in timed coincidence (resolving time
of a few nanoseconds), allowing a line of response to define
the cord along which the positron was annihilated (the location
of the emission is not known because of the short distance the
positron travels before annihilation). By mathematically backprojecting the lines of response, a density map can be generated
that reflects the distribution of the positron emitter.
There are several physical limitations inherent to PET
technology. Firstly, as the emitted positron has kinetic
energy, varying from a few hundred kiloelectronvolts to several
megaelectronvolts depending upon which radionuclide, it will
thus travel a few millimeters to centimeters before annihilating
with an atomic electron. As such, the site of annihilation
is not the site of emission, thus resulting in a limitation
when defining the origin of the decay. Another limitation
is the fact that the positron–electron pair is not at rest when
the annihilation occurs, thus by conservation of momentum,
the two photons are not exactly collinear. Although the lack
of co-linearity becomes increasingly important with greater
10
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
Figure 8. The three panels show a combined FDG PET/CT image in transaxial, saggital and coronal views, from left to right. The colored
hot metal image is the PET image and the gray image is from the CT camera. The combined image enables physicians to determine the
precious location of abnormal function (high uptake in the mass visible on the chest wall in the CT image in this case). Photo courtesy of
British Columbia Cancer Agency.
detector separation, this effect is ignored, for the most part, in
existing tomographs because the detector ring diameter is less
than a meter at which distance the deviation from 180◦ is a
fraction of a millimeter.
One of the major strengths that PET has over SPECT is
the ability to measure, directly, the attenuation effect of the
object being viewed. This is the result of requiring that both
photons are detected. Thus, if one photon of the pair is not
observed then there is no line of response. Along the path to the
detectors, one or both photons (511 keV each, the rest mass of
the electron) can undergo absorption by the photoelectric effect
or Compton scattering when interacting with surrounding
material. Thus, in order to be detected as an event, both photons
must be detected in temporal coincidence. By using an external
source of positron emitter, the attenuating (absorbing) extent
of the object to be measured can be determined. However
that advantage has been eliminated now that all commercial
PET (and many SPECT) cameras are built with a CT scanner
(x-ray tomography) so that a merged image of structure and
function can be obtained. In addition, as the CT image
is a measure of electron density, it is used to calculate the
necessary coefficients for attenuation correction. However,
the calculated attenuation coefficients are difficult to perform
in the thorax. Nevertheless, the use of the CT image is standard
for attenuation corrections now although its primary function
is to provide a detailed view of the section of the body under
investigation. Figure 8 illustrates the power of this approach.
Once the attenuation of the object is measured and the
radiotracer is injected the temporal and spatial distribution of
the tracer may be determined. However, to make a quantitative
estimate of the distribution there are other corrections required.
First of all, for true quantitative extraction of information the
detector system must be normalized to account for the nonuniform response of the detector system. This is achieved
by placing a cylindrical flood phantom of known tracer
concentration in the field of view and measuring the responses
of all detector pairs.
Other corrections are needed to account for scattered
photons, which for modern systems can be anywhere from
30% to 50% of the events. The amount of scatter can be
reduced by selecting a narrow energy window of acceptance
so as to eliminate large angle scatter (large angle scatter results
in lower energy of the scattered photon). This will however
reduce the efficiency. The remaining scatter profile is removed
by analytical techniques, a discussion of which is beyond this
review.
Finally, there are random coincidences that must be
subtracted. Because of the finite timing window for defining a
coincidence, there is the possibility of unrelated events arriving
within the timing window. The number of random events is
related to the size of the timing window and the count rate in
any one detector. Random events can be reduced by using fast
detectors and electronics which enable a short timing window
to be employed. Randoms are usually estimated by monitoring
the single event rate and subtracting globally from the image.
Once all of these corrections are applied the resulting
image can be displayed as what is called a parametric image.
In its simplest form this will be disintegrations per second
for the volume element of the image. If a mathematical
model is employed that describes the time course of the
tracer the images can be presented as metric describing a
biological function such as glucose metabolism when using
18
F-fluorodeoxyglucose (FDG) or the binding potential in
measuring receptor concentrations. The binding potential is
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T J Ruth
related to the ratio of the receptor concentration (Bmax ) and the
affinity of the tracer for the receptor (KD ).
The heart of the PET camera is the detection system.
The vast majority of modern PET scanners make use of
segmented inorganic scintillation crystals coupled to multiple
PMTs. The ideal crystal will have a high stopping power for the
511 keV annihilation photons (high photoelectric absorption),
a high light output with wavelength matched to the PMT, a
fast decay time for the light and be physically robust. For
nearly two decades the detector material of choice was bismuth
orthogermanate (BGO). More recently lutetium orthosilicate
(LSO) has been introduced. Due to its higher light output,
the segmentation of the crystals could be finer, thus reducing
the crystal element size from approximately (4 mm × 4 mm)
to (2 mm × 2 mm). There are proposals to reduce the crystal
elements to below 1 mm2 . In order to accomplish such a task,
the packing fraction of the crystals must be improved; in other
words, the empty space between crystal elements must remain
a small fraction of the total area.
The typical crystal is segmented into an 8×8 grid (or more)
coupled to four PMTs. There is an algorithm to identify the
location of the event by comparing the light sharing amongst
the PMTs. While this scheme reduces the cost of the scanner
there is a loss in resolution due to the approximate nature of
the light sharing approach. There are prototype scanners using
avalanche photodiodes coupled to individual crystal elements
making the finer pixel identification better. Thus far, such
systems have been built only for small animal scanners.
Functional imaging using PET started as a research tool
in neuroscience in the late 1970s and still remains a major
research tool for current-day neurosciences. However, its
major impact recently has been in the diagnosis of cancer.
While simple tracer molecules such as water, carbon monoxide
and carbon dioxide had been used for many years the first
complex molecule to be used extensively was the glucose
analog, 18 F-fluorodeoxyglucose (FDG), developed at the
Brookhaven National Laboratory (BNL) in collaboration with
researchers at the National Institutes of Health in the US and
the University of Pennsylvania around 1975. Since the human
brain uses glucose as its primary energy source, the availability
of the tracer led to ground-breaking work for studying the
human brain in health and disease. This effort was driven by
the successful use of 14 C labeled deoxyglucose at the NIH by
Louis Sokolov in the 1960s. Since 14 C is not detectable from
outside of the body, the effort went into developing a labeled
analog that could be shipped from a cyclotron facility (BNL in
this case) and the PET camera (the University of Pennsylvania).
Thus F-18 with its nearly 2 h half-life became the radionuclide
of choice.
Today, many more tracers are used to investigate the
various neuronal systems probing both the presynaptic and
the postsynaptic pathways. Several hundred tracers have been
prepared and tested for the utility in investigating various
enzymatic and receptor systems while only a handful are
routinely used. There are tracers specifically designed to
monitor cell proliferation, the hypoxic nature of cells and cell
apoptosis.
Because diagnostic imaging is driven by a digital approach
(present/absent, yes/no) the desire to have uncluttered images
Table 4. Radionuclides used in imaging for SPECT and PET
studies.
SPECT
PET
99 m
11
201
18
Tc
Tl
67
Ga
123
I
C
F
64
Cu
124
I
resulting from PET is of great importance. Nevertheless, the
true power of PET is its ability to track the distribution of a
tracer over time and extract detailed kinetic data as in a physical
chemistry experiment where rate constants are determined. So
the conflict between using the technology for clinical diagnosis
versus using PET as an in vivo biochemistry tool will not be
easily resolved, nor should it be.
With the advances in the technology enabling increasingly
better resolution, it has become possible to build PET scanners
capable of imaging small animals. The pharmaceutical
industry has recognized the power of using such small animal
PET scanners as a screening tool for their pre-clinical research.
PET can be used as a surrogate to monitor changes in
metabolism or receptor occupation or by labeling the drug
directly and determining the distribution and time course of
the compound, in vivo. One of the strengths of PET in this
regard is that animals can be used many times so that they can
serve as their own controls and changes due to interventions
monitored. Such an approach reduces the number of animals
required and increases the statistical power of the study. See
below for more details on small animal scanning.
Pharmaceutical companies also recognize that human
PET scanning can be used as surrogates for monitoring the
therapeutic efficacy of drugs in phase II and III drug trials.
By performing baseline scans and scans at intervals following
intervention, the PET data can often reveal biochemical
changes much sooner than the clinical signs—thus shortening
the assessment time. Most often surrogate markers are used to
monitor a particular functional change.
As the physical limitations of detection are approached,
the remaining avenue is to increase the signal to noise by
utilizing tracers that are uniquely suited to imaging the function
in question and otherwise clear rapidly from surrounding
tissue. To this end, the development of more specific tracers is
believed to be the most critical component for PET.
Radionuclides in imaging. While there is a wide range of
radionuclides that are used in imaging, a relatively small
number make up the vast majority of all studies in SPECT
and PET imaging. Table 4 lists the most widely used
radionuclides for imaging along with a couple of potentially
useful radionuclides.
For the SPECT agents, 99m Tc is the most widely used
accounting for approximately 80% of all studies in nuclear
medicine. This is primarily due to its availability through the
99
Mo/99m Tc generator as discussed earlier. Tl-201 is widely
used in cardiac studies as thallous chloride. The Tl+ ion is an
analog of K+ which is used in muscle function.
Ga-67 as a citrate is used to detect inflammation and I-123
is used in a variety of radiopharmaceuticals to image brain,
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T J Ruth
have high specific activity 123 I available for labeling. However,
the production costs are still relatively high in comparison with
other radionuclides, which will make its use limited for the
foreseeable future. While 123 I can be produced for local use
via the 123 Te(p,n) or 124 Te(p,2n) reactions, the co-production
of 124,125 I limits the product’s shelf-life.
Although 99m Tc can be produced on an accelerator its
production in a reactor by extraction of its parent, 99 Mo, from
235
U fission products is much cheaper and more efficient.
Thalium-201 has been extensively used for more than 30
years to assess cardiac blood flow as a K+ analog. Over this
period there have been numerous reports of its demise, yet the
growth in demand for this isotope is still upward.
The remaining isotopes listed are used in PET imaging.
Carbon-11 is extremely attractive because, in principle, one
can replace an existing carbon atom in the molecule of interest
with the radioactive isotope. However, because of the short
half-life, its availability will be limited to those sites that
either possess an accelerator or are close to an accelerator.
The demand for 18 F exceeds its availability. To overcome
this shortage, a number of central distribution centers have
been placed in large metropolitan areas in North America,
Europe and Asia. Although several nuclear reactions are
available, the (p,n) reaction is the route of choice for producing
large quantities of 18 F. If the availability of 18 F continues to
grow, 18 F-labeled compounds may begin to compete with other
SPECT agents such as 123 I.
The other two isotopes, 64 Cu and 124 I, are candidates for
both PET imaging and possible use in therapy (see below).
The interest in these two is primarily related to the relatively
long half-lives. Such properties would enable studies to be
performed where the in vivo kinetics are slow and exceed
the ability to image with 18 F. The disadvantages include low
production rate (124 I) and the need for expensive enriched
target material (64 Ni, 124 Te (<1% and <5% natural abundance,
respectively)). Results from Washington University in St Louis
have shown that even with the high-energy β + -particles
associated with 124 I decay and other photons in coincidence
with the β + -decay, they can still be imaged at high resolution
(64 Cu) (McCarthy et al 1997, Lewis et al 2003).
PET imaging has been in use for several decades for
human brain and whole body imaging, first only as a research
tool, now gaining acceptance as a diagnostic imaging modality
in selected applications such as oncology and, very recently,
as an aid in the diagnosis of Alzheimer’s disease. All of
these advances are made possible through the improvement in
resolution and sensitivity of the scanners but more importantly
by the development of more specific tracers.
Table 5. Nuclear reactions used to produce imaging radionuclides
from accelerators.
Radionuclide
t1/2
Reaction
99m
6.0 h
13.1 h
100
123
Tc
I
201
Tl
C
73.1 h
20.3 m
18
F
110 m
64
Cu
12.7 h
11
124
I
4.14 d
Mo (p,2n)
Xe(p,2n)123 Cs
124
Xe(p,pn)123 Xe
124
Xe(p,2pn)123 I
123
Te(p,n)123 I
124
Te(p,2n)123 I
203
Tl(p,3n)201 Pb→201 Tl
14
N(p,α)
11
B(p,n)
18
O(p,n)
20
Ne(d,α)
nat
Ne(p,X)
64
Ni(p,n)
68
Zn(p,an)
nat
Zn(d,axn)
nat
Zn(d,2pxn)
124
Te(p,n)
125
Te(p,2n)
124
Energy
(MeV)
30
27
15
25
29
11–19
10
15
14
40
15
30
19
19
13
25
heart and kidney function. The variety of compounds available
is based on the ability to chemically insert iodine into complex
molecules.
Of the PET radionuclides F-18 is by far the most widely
used, principally due to its use in FDG. The fluorine atom is
about the same physical size as the hydrogen atom in most
molecules; thus F-18 is used as a hydrogen substitute. A large
number of molecules have been labeled with F-18. C-11 is
also widely used because of the obvious isotopic substitution
for C-12. The principal disadvantage of C-11 is its short
half-life (20 min) which limits its availability to sites with an
accelerator. Cu-64 has a half-life of just over 12 h and is thus
of interest to probe systems which have a long biological halflife. I-124 has the advantage of being easily inserted in a wide
range of molecules but its 4 d half-life limits its utility due to
high radiation exposure.
Table 5 provides various low energy production routes
along with the half-life of the radionuclides. Technetium99m is included since this isotope alone accounts for nearly
80% of all nuclear medicine imaging studies. There have
been a number of proposals suggesting that 99m Tc could
be produced at an accelerator. However, the economics of
accelerator production cannot compare with the extremely low
costs of producing it at a reactor. While there is concern about
the ability to build new reactors and the availability of this
important isotope may be jeopardized, the recent construction
of reactors in Canada dedicated to 99 Mo production and the
upgrade of other facilities around the world will remove this
concern for the present.
Iodine-123 has been of interest for nearly three decades
because of its unique chemistry that makes it possible to attach
this isotope to a wide variety of molecules and the γ -ray energy
(159 keV) that is matched well to SPECT cameras. The ability
to produce this isotope in high purity from enriched 124 Xe
targets made it possible to ship 123 I over long distances and still
Small animal scanning (Sossi and Ruth 2005). Compared
with human PET scanning, small animal PET presents new
challenges, both of instrumentation and biological nature.
However, it also offers the possibility of performing in vivo
testing of new pharmaceuticals while at the same time allowing
for the possibility of direct correlation between in vivo and
in vitro measurements thus indirectly providing a deeper
understanding of the human PET measurements. For the most
part the use of small animal scanning has been dominated by
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Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
metabolism via the use of the labeled drug or to measure
the efficacy of action through the use of other PET tracers
as surrogate markers of the drug role in altering function
(Langstrom et al 1995). While labeling the drug directly
may present some challenges, the labeled drug is seen as an
important tool for those compounds directed at brain function
since an estimate of the degree that (and even whether) a drug
penetrates the blood–brain-barrier is required before further
drug assessment. In addition, the concentration at which a
drug has an effective action is often associated with plasma
concentrations when in fact this relationship may not really be
measuring the effect of the drug in the brain. The true effect
can be measured via PET, either with labeled drug or with
surrogate molecules.
In drug design a particular neuronal system is to be
altered through blocking enzymes, intercepting transmitters
or occupying receptors. Using tracers that are sensitive to
these changes can provide the needed information in a time
frame measured in minutes to hours as opposed to waiting for
a pharmacological effect which may take days if not weeks.
As mentioned in the introduction, the ability to assess the
effects of an intervention longitudinally, on the same animals,
significantly reduces the variability of the final results and
makes better and more efficient use of the animals themselves.
d. Comparison with post-mortem measures.
A unique
advantage of small animal imaging is the ability to use the
same animal as its own control and to perform longitudinal
studies. In more traditional animal studies multiple animals
were required at various time points so that the animals could
be sacrificed and studied to determine the time course of the
function under investigation. With small animal scanning
the time course can be measured directly, even over days
if necessary. The challenge with longitudinal studies is to
reposition the animal so that the regional data are correlated.
e. Radiotracer and chemistry development. Future advances in
functional imaging using nuclear techniques, especially PET,
are dependent on tracer development. The PET scanner only
measures radioactive decays and cannot by itself identify a
biological process of interest. To understand the time course of
the tracer, the careful design and development of the radiotracer
to make it as specific as possible for the relevant biological sites
and processes, while minimizing nonspecific binding to other
tissue types, is required (Okarvi 2001, Kawamura 2003). As
the imaging instrumentation becomes more powerful, there
is an increasing demand for new tracers as more sites and
processes become potentially observable in vivo. In addition to
undergoing in vitro validation however, the new tracers must
undergo a rigorous validation of their in vivo behavior and,
where necessary, new imaging protocols and analysis methods
must be developed. Presently there are a number of small
molecules that have been used in human PET scanning for
years as well as in small animal autoradiographic studies using
the 3 H- and 14 C-labeled versions. In order to have sufficient
signal for the PET scanner the tracers have to be of sufficiently
high specific activity (radioactivity units per mass) to provide
a high-count rate while not violating the tracer principle. The
specific activity required to maintain this principle is on the
order of 37 GBq µmol−1 (Hume et al 1998). Thus when
research in oncology because of the existing animal models
of tumor biology and the relative ease of placement of the
tumor in a location with low background. With the increased
availability of animal models of disease especially in cancer
biology where a wide variety of tumor models are not only
being developed but mice are being genetically modified to
spontaneously produce tumors, small animal imaging is being
used to test new therapies as well as developing more specific
diagnostic tests. In addition, small animal imaging has been
steadily expanding into the areas of brain and neuroreceptor
imaging with a variety of different tracers.
The challenges associated with small animal scanning can
be divided into the physical and biological issues as discussed
below.
a. Instrumentation related challenges.
The biggest
instrumentation challenge that needed to be overcome to
successfully apply PET imaging to small animals was to
increase spatial resolution, while still maintaining high
detection sensitivity. For example, the spatial resolution of
traditional human PET scanners ranges typically from (4 mm)3
to (9 mm)3 , while the size of a rat or mouse organ is orders of
magnitude smaller compared with the size of the corresponding
human organ.
b. Biology related challenges. The small size of the animals
limits the amount of the tracer that can be administered in
a scanning session: PET is based on the tracer principle,
that is, the administered radiotracer must not influence the
process under investigation. In receptor imaging this is
satisfied when the tracer does not occupy more than 1% of
the available receptors (Hume et al 1998). This requires
tracers to be produced at very high specific activities (generally
>37 GBq µmol−1 ) and limits the amount of radioactivity that
can be injected, thus rendering detection sensitivity even more
important.
The second complication due to the small physical size
is the fact that the size of the animal’s blood pool is very
small. This has direct implications on the applicability of
biological models that are applied to the PET data to extract
biologically relevant parameters such as binding potentials and
process rate constants. Many of these models in fact rely on
an input function derived from the radiotracer concentration in
plasma, measured by the extraction of several blood samples.
Such blood sampling is often not possible with these small
animals; therefore, analysis methods that utilize tissue input
functions must be used. Such methods require a region where
there is no specific binding of the tracer and appropriate regions
must be accurately identified for each tracer. Conversely, some
research groups are looking into the possibility of measuring
the plasma input function from the image of an animal organ,
such as the heart (van der Weerdt et al 2001). However,
this is in practice only feasible when the radiotracer does not
undergo significant metabolism: the PET scanner only detects
radioactivity and is not able to separate the chemical form of
the radioactively labeled substance.
c. Testing of new drugs and their efficacy. Small animal PET
imaging is an ideal tool in the process of new drug development
and evaluation of treatment efficacy (Campbell 1995). PET
imaging can be used to either follow a drug distribution and
14
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
Figure 9. Placement of the PET insert inside a 7-T MRI scanner: photograph (a) and drawing (b) show magnified views of insert and the RF
coil in place inside the MR scanner and drawing (c) shows axial placement (Catana et al 2006).
Figure 10. Black and white MRI images and merged FDG PET images with the MRI scans (Judenhofer et al 2007).
injecting a few MBq of a tracer with such specific activities
the resulting mass of the injected tracer would be on the order
of tens of picomoles. In addition to the need for high specific
activity there is a need for high radioactivity concentration
(radioactivity units per volume of solution). This requirement
stems from the fact that the volume that can be injected into
rodents is on the order of 0.5 mL, maximum because of the
small blood volume of the animal (typically 20 mL for rats and
2 mL for mice). While there are no requirements to produce
the tracers under regulatory conditions, it is obvious that the
tracer must be of the highest purity in order to preserve the
integrity of the study (Sossi and Ruth 2005).
Just as with human scanning, small animal PET has been
combined with CT scanners. However, there is a complication
associated with the high radiation dose from the CT adversely
affecting the animal under investigation. Thus the power of
the x-ray beam must be monitored, especially if the animals
are to have serial scans. Nevertheless the images are exquisite.
To overcome this difficulty and to provide even more
information in a single setting investigators are developing
combined PET-MRI devices. Unlike the PET/CT systems
which are two scanners built back-to-back, the PET/MRI
systems are integral as shown in figure 9.
The development of this technology is moving forward
rapidly and is being applied to human studies as well as
illustrated in figure 10 which shows early images from an F-18
FDG scan.
4.5. Radionuclides for therapy
The idea of a radionuclide used in therapy is based on the
desire to link a radionuclide which has a high linear energy
transfer associated with its decay products such as Auger
electrons, β-particles or α-particles to a biologically active
molecule that can be directed to a tumor site. Since the
β − -emitting radionuclides are neutron rich they have, in
general, been produced in reactors although a few are best
produced via charged particle reactions. Astatine-211 is one
such radionuclide [209 Bi(α,2n)211 At]. Table 6 provides a list
of radionuclides considered suitable for therapy along with
their physical characteristics while table 7 contains the nuclear
reactions that can be used for selected radiotoxic nuclides.
The attractive feature of 77 Br is its chemical versatility
in addition to its half-life. Production rates are relatively low
and purity may be an issue since 76 Br is often co-produced.
The demand for 103 Pd, which is used in treating prostate
cancer, is continuing to grow. A large number of low energy
(19 MeV) cyclotrons are dedicated solely to the production of
this isotope.
Yttrium-90 is an attractive radionuclide for therapy
because it is a pure β − emitter and is the product of 90 Sr decay.
Strontium-90 has a long half-life (28.8 years) and is readily
available as a fission product from nuclear reactors. Because
Y-90 does not have an imageable γ -ray, another isotope of
yttrium or one of similar chemical properties must be used. In
most instances 111 In has been used as the surrogate.
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Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
Table 6. Radionuclides that have been proposed for use as possible
radiotoxic isotopes for treating cancer.
Isotope
Half-life (h)
Bromine-77
Iodine-131 (131 I)
Yttrium-90 (90 Y)
Lutetium-177 (177 Lu)
Copper-67 (67 Cu)
Rhenium-186 (186 Re)
Rhenium-188 (188 Re)
Bismuth-212 (212 Bi)
Bismuth-213 (213 Bi)
Astatine-211 (211 At)
Actinium-225 (225 Ac)
58
192
64
161
62
90.5
16.9
1
0.77
7.2
240
Receptor
Emission
(for therapy)
Auger electrons
β
β
β
β
β
β
α
α
α
α
Antibody
Cancer Cell
Figure 11. Schematic illustrating the antibody labeled with a
radiotoxic isotope and how the antibody targets specific receptors on
the cancer cell. As the radioisotope decays there is a high
probability that some of the beta particles will break the DNA
strands in the cell nucleus initiating cell death (drawing courtesy of
S Lapi, Simon Fraser University, Burnaby, Canada).
Table 7. Production routes for selected therapy radionuclides.
Radionuclide t1/2
77
90
Br
Y
103
Pd
186
Re
211
At
2.4 d
Decay
mode
Auger
electrons
Reaction
Energy
(MeV)
α-particle associated with it. Because of its short half-life
multiple production sites would be required. Thus the interest
in producing its parent radionuclide (211 Rn, t1/2 = 14.6 h) has
been suggested as a way of producing and shipping 211 At to
remote sites.
In spite of its long half-life there is growing interest in the
use of Ac-225. The concern with the long half-life is related
to the redistribution that may occur during its residence in the
body following a therapeutic injection.
75
As(a,2n)
Se(p,n)
78
Se(p,2n)
79,81
Br(p,xn)77 Kr
nat
Mo(p,spall.)
90
Sr decay
27
13
24
45
>200
−
2.7 d β
Sr-fission
product
103
17.5 d Auger
Rh(p,n)
19
electrons nat Ag(p,xn)
>70
185
90.6 h β¯
Re(n,γ )
Thermal
186
W(p,n)
18
186
W(d,2n)
20
197
Au(p,spall.)
>200
nat
Au(p,spall.)
>200
nat
Ir(p,spall.)
>200
209
7.2 h α
Bi(α,2n)
28
209
Bi(7Li,5n)211 Rn 60
232
Th(p,spall.)211 Rn >200
77
4.5.1. Targeted radionuclide therapy. In order for these
radionuclides to be effective at cancer cell killing, they must
either be located at or near the cancer cells (high LET particles)
or near the DNA in the nucleus (Auger emitters). Major
research efforts have gone into finding the magic bullet, that
is achieving site directed delivery of the radionuclide. Most
efforts have centered on the use of monoclonal antibodies that
are substrates for specific receptors associated with specific
cancer cells. Receptors are proteins usually on the cell surface
that are used by the cell that act like signal transducers, receive
chemical signals from other cells, thus acting as receptors of
chemical information. Each of these receptors has unique
chemical and physical (spatial) properties so that only certain
molecules can be bound or received by the receptor. A
close analogy is a lock and key concept. Recently two
commercial products have appeared on the market that are
based on this concept, antibodies labeled with radionuclides
(Zevalin® , labeled with 90 Y (t1/2 = 2.7 d) and Bexxar® labeled
with 131 I(t1/2 = 8 d)) (Health Canada (Bexxar) 2005; Health
Canada (Zevalin) 2005).
Figure 11 illustrates the steps in targeting cancer cells
with labeled antibodies. The radionuclide must be attached
to the antibody in such a way as not to impact the recognition
properties of the antibody for the specific receptor on the cancer
cell. With β-particle radiation the damage does not have to
occur on the cell on which the antibody is attached. With the
range of particles representing a few cell diameters there is the
possibility of damage to neighboring cells. This concept is
referred to as the crossfire effect.
Rhenium-186 is attractive for a number of reasons. It has
the desirable physical characteristics of being a β − -emitter
with a useful half-life (90 h) and a γ -ray (137 keV) that
can be imaged with standard SPECT cameras. This ability
to be imaged provides a strong case for its use since
radionuclide therapy agents are often pure β¯ emitters and
require a surrogate radionuclide for distribution information.
In addition, rhenium is in the same chemical family as
is technetium; thus much of the chemistry developed for
technetium can be applied to rhenium. The production from
the neutron capture reaction leads to a low specific activity
product which limits its shelf-life and may also limit its utility
as a radiotoxic species when attached to a chemical vehicle
such as an antibody. Production rates from all of the reactions
from charged particles for this radionuclide listed in table 7
are very low. Thus the only practical route to this potentially
important radionuclide is via neutron capture in a reactor.
And finally, α-emitting isotopes have been of interest
for use in therapy because of the high LET associated with
the α-decay. Astatine is of interest because it possesses
many properties of halogens and each decay of 211 At has an
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T J Ruth
neurotransmission, receptor density and occupancy have all
been measured via appropriately designed radiotracers. It
should be pointed out that the development of radiotracers
for PET fundamentally violates rule number 2 for the ideal
tracer because PET radionuclides, by nature, emit β + particles.
However, the resulting coincident γ -rays from β + annihilation
form the basis for the technique.
In addition to consideration of the above principles, the
radiochemist must plan how to insert the radionuclide into
the molecule at a point in the synthetic process where there
is minimal handling, yet late enough in the synthesis to
minimize loss due to chemical yield and radioactive decay. For
these reasons the preparation of radiopharmaceuticals requires
planning and techniques not encountered by traditional
synthetic chemistry.
The development and use of PET tracers can be viewed
as covering two major areas: (1) tracers that can be used as
surrogate markers for biological processes and (2) those tracers
that are specific for a particular process, whether it is intended
to measure enzyme activity or receptor concentration or the
expression protein synthesis. A major hindrance in tracer
development is the complex nature of the synthesis process
itself. While major steps have been made to simplify the
synthetic steps there are still areas in need of improvement
such as miniaturization of the synthesis instrumentation.
Miniaturization provides the opportunity to use small amounts
of starting materials and radioactivity that would make the
purification simpler and easier. Simple solid phase columns
could be used instead of cumbersome high performance liquid
chromatography. In addition, if the miniaturization can be
realized it is conceivable that multiple compounds could
be prepared in parallel for testing with a single supply of
radionuclide. This can be viewed as the radiochemist’s attempt
at screening compounds.
5. Radiopharmaceuticals
The term radiopharmaceutical is applied to a biologically
active compound that either has a radionuclide attached or
in the elemental form behaving as a radiotracer that can be
safely administered to humans. The safety of these molecules
is determined by their radionuclidic and radiochemical purity
and that they are sterile and free from micro-organisms that
can cause fevers (pyrogens).
Radiopharmaceuticals differ in one major aspect from
regular pharmaceuticals in that they are given in such small
concentrations that they do not elicit any pharmacological
response. Because of this there have been a number of attempts
to change the name used to describe these substances to,
for example, radiotracers. Present-day radiopharmaceuticals
are used for diagnostic purposes in about 95% of the cases
and the remainders are used in therapy. However the use of
radiopharmaceuticals in therapy is seen as the next major area
for growth in the use of radionuclides.
In order for a radiotracer (radiopharmaceutical) to be used
in humans safely it must meet the quality standards that include
chemical and radiochemical purity and it must be sterile and
free from pyrogenic material.
The ideal radiopharmaceutical for imaging should
(1) be readily available at a low cost,
(2) be a pure gamma emitter, that is no α and β (such particles
contribute radiation dose to the patient while not providing
any diagnostic information, (see the section on dosimetry);
this is, of course, not followed with PET),
(3) have a short effective half-life so that it is eliminated from
the body as quickly as possible,
(4) have a high target to non-target ratio so that the resulting
image has a high contrast, that is the background does not
blur the image,
(5) possess proper metabolic activity in that it follows or is
trapped in the metabolic process of interest.
6. Environmental/biological applications
Radioisotopes can be used to help understand chemical and
biological processes in the environment and in plants. There
are two reasons for this usefulness. Radioisotopes are
chemically identical to other isotopes of the same element
and will react in the same way in chemical reactions and for
many elements some radioactive isotopes of the element have
appropriate half-lives and can be easily detected. In other
situations elements or simple molecules can be constructed
to have similar chemical or physical properties of the chemical
systems to be probed. In using surrogate markers their use
needs to be validated through experimentation.
The ability to measure regional biochemical function requires a
careful design process with these principles in mind. However,
in reality it is not possible to meet all of these criteria. For
example, all decay processes involve the emission of particles
as in the case of pure γ -emitters which have Auger electrons
emitted during some fraction of the decays. Thus, it is
necessary to address the following steps (Eckelman and Gibson
1993) in the development of a biochemical probe:
(1) develop a radiotracer that binds preferentially to a specific
site;
(2) determine the sensitivity of the radiotracer to a change in
biochemistry;
(3) find a biochemical change as a function of a specific
disease that matches that sensitivity.
6.1. Agricultural applications
There are many applications of radioisotopes in agriculture.
Radiation has been used to breed new seed varieties with higher
yields, such as the ‘miracle’ rice that has greatly expanded rice
production in Asia. The ionizing radiation from radionuclides
increases the number of variations in plants and, with careful
selection, can produce crops that are more drought and disease
A large number of radiotracers have been synthesized to probe
metabolic turnover such as oxygen consumption, glucose
utilization and amino acid synthesis. Enzymatic activity,
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T J Ruth
resistant, as well as crops with increased yield or shorter
growing time. This practice has been in place for several
decades and has helped feed some third-world countries.
Radioisotopes are ideally suited as tools for the
investigations of fertilizers. Important plant nutrients, such
as calcium, phosphorus, iron, potassium, copper, sodium,
sulfur, and zinc, have radioisotopes with appropriate halflives and decay characteristics to be used as tracers. These
elements can be incorporated in fertilizers and applied to the
soil to determine the effect on plant utilization of fertilizer
composition or the method of application. Plant uptake of
the activated fertilizer can be readily measured and can be
distinguished from the uptake of the same compound already
present in the soil.
See the section below on plant physiology which
explores some fundamental mechanisms that affect plant
interactions with the environment, both natural as well as
artificial.
at the same time reducing harmful environmental effects of
excessive nitrogen use.
All of these studies involved using N-13 labeled nitrate
and or ammonia in the lab under controlled conditions.
The use of C-11 (t1/2 = 20.3 min) provides the
opportunity of producing more complex molecules as is seen
in the medical applications discussed earlier.
This example illustrates how the use of radiotracers has the
potential to impact what is understood about plant physiology
and the effect of nutrients in the environment. Details of these
studies and more are provided in the readings listed.
6.3. Earth and ocean sciences
Radiotracers are used studying the biological production
in aquatic environments. For example, Si-32 is used to
estimate the rates of silicon uptake by diatoms. Diatoms, a
group of aquatic algae, are one of the largest contributors to
carbon fixation accounting for up to 75% of marine primary
production. They have absolute requirements for silicon,
which is precipitated as amorphous hydrated silica in their
cell walls. Hence, diatoms control the cycling of silicon and
contribute significantly to the downward flux of biologically
produced silica, nitrogen and carbon in most oceanic regions.
Accurate determination of diatom growth is essential for
understanding global nutrient cycling and biogeochemical
modeling.
Another radiotracer that is being used to further our
understanding of the carbon cycle and the oceans is Cu-67. Iron
(Fe) is an essential micronutrient for phytoplankton growth
and has been shown to control primary productivity in large
oceanic regions. However the role of copper in this process
is poorly understood. With the Cu-67 62 h half-life it has
become possible to use this isotope as a tracer in deep ocean
studies without having to store and transport the samples back
to the lab.
6.2. Plant physiology
Probably the most widely used tracer for studies in tracer
kinetics in plants is N-13. In spite of its relatively short
half-life (<10 min) a wide variety of studies have been
undertaken to understand the incorporation of nitrogen into
plant systems (Britto 2004). These studies have had a wide
impact on understanding the adaptive abilities of plant systems
associated with changing environmental conditions to monitor
the nitrogen content of genetically modified rice in attempts
to increase the protein content of rice species as the primary
protein food around the world.
By examining the roots of rice plants and the manner in
which cellular pools of carbohydrates and various nitrogen
compounds regulate the expression of three ammonium
transporter genes by measuring the ammonium influx using
13
NH+4 , the researchers found that N and C interact at the
cellular level so that the supply of N provided by the root
ammonium transporters matches the availability of carbon
compounds provided by leaf photosynthesis.
This research team has investigated the effect of different
transport systems in the root system by genetically modifying
Arabidopsis (a small flowering plants related to cabbage and
mustard) to express one of the two transporter genes. They
have demonstrated that one mutant is unable to grow normally
when the nitrate is the sole source of N and that the 13 NO−
3
uptake is dramatically reduced. Thus high-affinity nitrate
uptake requires participation of genes encoding both the type
of transporter proteins.
A large portion (perhaps >50%) of applied nitrogen
fertilizer is lost from soils. One significant proportion of this
loss is attributed to ammonium blocking nitrate uptake. Using
the fungus Aspergillus as a model system this team studied the
mechanism of this effect. They found that the effect is rapid
and due to ammonium per se not to its metabolic product, e.g.
glutamine. They are investigating whether the protein can be
modified so it can be eliminated in transgenic plants to reduce
nitrate losses from soil and improve fertilizer utilization while
6.4. Insect control
About 10% of the world’s crops are destroyed by insects.
These pests can sometimes be controlled by releasing sterile
laboratory-raised insects into the wild. The male insects are
made sterile using ionizing radiation. Female insects that
mate with sterile male insects do not reproduce, and the
population can be quickly curbed as a consequence. The
technique is considered to be safer and better than conventional
chemical insecticides since insects can develop resistance
against insecticides, and there can be health concerns about
chemically treated crops.
6.5. Water resources
Adequate water is essential for life. However in many parts of
the world water is scarce and in others it is becoming scarcer.
Isotope hydrology makes accurate tracing of underground
water resources possible. These techniques are important
analytical tools in the management and conservation of existing
water supplies and in the identification of new, renewable
sources of water. The results permit planning and sustainable
18
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
Table 8. Common radionuclides and their uses.
Calcium-47
Carbon-11,14
Cesium-137
Chromium-51
Cobalt-57
Copper-64
Fluorine-18
Gallium-68
Germanium-68
Iodine-123
Iodine-129
Iodine-131
Nitrogen-13
Oxygen-15
Phosphorus-32
Rubidium-82
Selenium-75
Sodium-24
Strontium-85
Technetium-99m
Thallium-204
Tritium (H-3)
Uranium-235
Uranium-238
Xenon-133
Yttrium-90
Aid to biomedical researchers studying the cell function and bone formation of mammals.
Used in research to ensure that potential new drugs are metabolized without forming harmful by-products.
Used to treat cancers; to calibrate the equipment used to measure correct patient dosages of radioactive
pharmaceuticals; to measure and control the liquid flow in oil pipelines; to tell researchers whether oil wells are
plugged by sand and to ensure the right fill level for packages of food, drugs and other products. (The products
in these packages do not become radioactive.)
More recently, Cs-137 has become the radioactive source by which attenuation is measured in PET scanners.
Used in research in red blood cell survival studies.
Used in nuclear medicine to help physicians interpret diagnostic scans of patients’ organs and to diagnose
pernicious anemia.
MicroPET scanners make use of Co-57 as the radioactive source by which attenuation is measured in small
animals.
Used in small animal PET imaging. Considered a potential radiotherapeutic.
Primary radionuclide used in PET imaging, generally substituted for hydrogen in biologically active molecules.
Generator produced PET radionuclide.
In equilibrium with its positron emitting daughter has been used as an attenuation source for PET scanners as well
as a source for Ga-68.
Widely used to diagnose thyroid disorders.
Used to check some radioactivity counters in in vitro diagnostic testing laboratories.
Used to diagnose and treat thyroid disorders such as Graves’ disease.
In the chemical form of ammonia N-13 is used as a blood flow marker in cardiac studies. Also used in plant
−
+
physiology studies (NO−
2 , NO3 and NH4 ).
Used in brain studies in various chemical forms to monitor blood flow (H2 O), Oxygen metabolism (O2 ), and
blood volume (CO)
Used in molecular biology and genetics research.
Used as a potassium analog to measure cardiac blood flow with PET
Used in protein studies in life science research.
Used to locate leaks in industrial pipelines and in oil well studies.
Used to study bone formation and metabolism.
The most widely used radioactive isotope for diagnostic studies in nuclear medicine. Different chemical forms
are used for brain, bone, liver, spleen and kidney imaging and also for blood flow studies.
Measures the dust and pollutant levels on filter paper and gages the thickness of plastics, sheet metal, rubber,
textiles and paper.
Used for life science and drug metabolism studies to ensure the safety of potential new drugs; for self-luminous
aircraft and commercial exit signs; for luminous dials, gauges and wristwatches and to produce luminous paint.
The source of Tc-99m and other important medical radionuclides when the U-235 undergoes fission.
Used in dental fixtures such as crowns and dentures to provide natural color and brightness and in fuel for nuclear
power plants and naval nuclear propulsion.
Used in nuclear medicine for lung ventilation and blood flow studies.
Radiotherapeutic nuclide used in combination with antibodies to treat cancer.
management of these water resources. Neutron probes
can measure soil moisture very accurately, enabling better
management of land affected by salinity, particularly with
respect to irrigation.
For surface waters they can give information about
leakage through dams and irrigation channels, the dynamics
of lakes and reservoirs, flow rates and river discharge rate
measurements and silt sedimentation rates. Many countries,
developed and developing, have used isotope techniques to
investigate their water resources in collaboration with the
IAEA.
imaging, while the big challenge in the next few years
will be for the chemists to develop tracers that are more
specific and reflective of the functional condition under
investigation, while miniaturizing the chemical synthesis and
related instrumentation.
Two major areas related to tracer development will include
the miniaturization of the chemistry for preparing tracers. With
the advent of microfluidics and lab-on-a-chip technology, the
automated syntheses of tracers on a wafer that can be discarded
are not far away. Such developments will speed the availability
of tracers for widespread human use because of the possibilities
of mass production of the miniature chemistry sets under
sterile conditions much like other medical devices such as
syringes.
The other area ripe for exploitation is in achieving higher
specificity of the tracer. This will most likely occur in the
use of peptides (protein fragments) and oligonucleotides or
short strands of DNA, which will be specific for a particular
gene expression for protein syntheses related to pathological
conditions. Being able to clearly identify a phenotypic disease
in a population could overcome some of the shortcomings
related to PET’s lack of sensitivity. Having a tracer that has a
very high signal relative to the background enhances the ability
7. Concluding remarks
Table 8 illustrates the vast variety of uses for radioactive
substances, some of which are obscure while others are
essential in modern life. The list is not comprehensive and
only represents those associated with life sciences. An equal
list can be generated for the physical sciences.
The future in imaging now lies in the development
of multi-modality imaging approaches such as PET/CT,
SPECT/CT and PET/MRI, as well as the use of optical
19
Rep. Prog. Phys. 72 (2009) 016701
T J Ruth
to detect small quantities, thus increasing apparent sensitivity.
In addition, this approach would truly introduce personalized
medicine since the compounds used would be unique to the
individual being examined.
While the use of radioactive species has become
widespread in the health field their use in other fields is still
relatively rare. This review paper tried to illustrate the power
associated with using radiotracers in a variety of disciplines,
both in basic research and in practical applications. While most
of the non-medically related applications of radiotracers have
used reactor produced species because of their availability,
the use of accelerator produced tracers has the potential for a
much wider use because of the introduction of PET as a routine
diagnostic modality around the world. This advance has placed
a very large number of cyclotrons around the world capable of
producing a wide variety of short-lived radionuclides for use in
the variety of disciplines described here. The only limitation
is the imagination of the investigator.
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Acknowledgments
Some of this material has appeared in other forms written by
the author. The author wishes to thank the large number of
people with whom he has collaborated over the years and who
have helped in the preparation of this document, in particular
Drs David Schlyer, Suzy Lapi, Vesna Sossi and Ms Katie
Gagnon for sharing information and helping with the text.
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Glass A D M, Britto D J, Kaiser B N, Kronzucker H J, Kumar A,
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Tai Y C, Chatziioannou A F, Yang Y, Silverman R W, Meadors K,
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Imaging in Drug Discovery, Development and Approval
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CRC Press)
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Neuroreceptors, Neurotransmitters and Enzymes (New York:
Raven)
Harbert J and da Roche A F G 1984 Textbook of Nuclear Medicine,
Volume I: Basic Science 2nd edn (Philadelphia: Lea and
Febiger)
Swanson D P, Chilton H M and Thrall J H 1990 Pharmaceuticals in
Medical Imaging (New York: Macmillan)
Imaging
Eckelman W C and Gibson R E 1993 The design of site-directed
radiopharmaceuticals for use in drug discovery Nuclear
Imaging in Drug Discovery, Development and Approval
ed H D Burns et al (Boston: Birkhäuser) pp 113–34
Lyons S K 2005 Advances in imaging mouse tumour models in vivo
J. Pathol. 205 194–205
Saha G B 1979 Fundamentals of Nuclear Pharmacy (New York:
Springer)
Small animal imaging
Campbell B 1995 Drug development and positron emission
tomography PET for Drug Development and Evaluation
ed D Comar (Dordrecht: Kluwer)
Chatziioannou A F 2002 PET scanners dedicated to molecular
imaging of small animal models Mol. Imaging Biol. 4 47–63
Cherry S R and Gambhir S S 2001 Use of positron emission
tomography in animal research ILAR J. 42 219–32
Cherry S R 2001 Fundamentals of positron emission tomography
and applications in preclinical drug development J. Clin.
Pharmacol. 41 482–91
del Guerra A and Belcari N 2002 Advances in animal PET scanners
Q. J. Nucl. Med. 46 35–47
Frese T, Rouze N C, Bouman C A, Sauer K and Hutchins G D 2003
Quantitative comparison of FBP, EM, and Bayesian
reconstruction algorithms for the IndyPET scanner IEEE
Trans. Med. Imaging 22 258–76
Herschman H R 2003 Molecular imaging: looking at problems,
seeing solutions Science 302 605–8
Herschman H R 2004 PET reporter genes for noninvasive imaging
of gene therapy, cell tracking and transgenic analysis Crit. Rev.
Oncol./Hematol. 51 191–204
Hume S P, Gunn R N and Jones T 1998 Pharmacological constraints
associated with positron emission tomographic scanning of
small laboratory animals Eur. J. Nucl. Med. 25 173–6
Hume S P and Myers R 2002 Dedicated small animal scanners: a
new tool for drug development? Curr. Pharm. Des. 8 1497–511
Jacobs A H et al 2003 PET-based molecular imaging in
neuroscience Eur. J. Nucl. Med. Mol. Imaging 30 1051–65
Jeavons A P, Chandler R A and Car D 1999 A 3D HIDAC-PET
Camera with Sub-millimetre resolution for imaging small
animals IEEE Trans. Nucl. Sci. 46 468–73
Knoess C et al 2003 Performance evaluation of the microPET R4
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Radiotracers
Qaim S M and Coenen H H (ed.) 2004 Advances in Nuclear and
Radiochemistry (Jülich: Forschungzentrum, Jülich GmbH)
Environmental
Albrecht A, Schultze U, Bello Bugallo P, Wydler H, Frossard E and
Flühler H 2003 Behavior of a surface applied radionuclide and
a dye tracer in structured and repacked soil monoliths
J. Environ. Radioact. 68 47–64
Ban-nai T and Muramatsu Y 2002 Transfer factors of radioactive
Cs, Sr, Mn, Co and Zn from Japanese soils to root and leaf of
radish J. Environ. Radioact. 63 251–64
Brandtberga P-O, Bengtssonb J and Lundkvist H 2004 Distributions
of the capacity to take up nutrients by Betula spp. and Picea
abies in mixed stands Forest Ecol. Management
198 193–208
Reide Corbetta D, McKeeb B and Duncan D 2004 An evaluation of
mobile mud dynamics in the Mississippi River deltaic region
Mar. Geol. 209 91–112
Seebaugh D R, Goto D and Wallace W G 2005 Bioenhancement of
cadmium transfer along a multi-level food chain Mar. Environ.
Res. 59 473–91
Wolterbeek H Th and van der Meer A J G M 2002 Transport rate of
arsenic, cadmium, copper and zinc in Potamogeton pectinatus
L.: radiotracer experiments with 76 As, 109,115 Cd, 64 Cu and
65,69m
Zn Sci. Total Environ. 287 13–30
21
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Botany
Chen X, Gastaldi C, Siddiqi M Y and Glass A D M 1997 Growth of
a lettuce crop at low ambient nutrient concentrations: a strategy
designed to limit the potential for eutrophication J. Plant
Nutrition 20 1403–17
Crawford N M and Glass A D M 1998 Molecular and physiological
aspects of nitrate uptake in plants Trends Plant Sci.
3 381–95
Min X, Siddiqi M Y, Guy R D, Glass A D M and Kronzucker H J
1998 Induction of nitrate uptake and nitrate reductase in
trembling aspen and lodgepole pine Plant Cell Environ.
21 1039–46
Kronzucker H J, Guy R D, Kirk K, Siddiqi M Y and Glass A D M
1998 Effects of hypoxia on 13 NH+4 uptake in rice roots:
kinetics and compartmental analysis Plant Physiol.
116 581–7
Kronzucker H J, Siddiqi M Y and Glass A D M 1997 Conifer root
discrimination against soil nitrate and the ecology of forest
succession Nature 385 59–61
Glass A D M, Erner Y, Kronzucker H J, Schjoerring J K,
Siddiqi M Y and Wang M Y 1997. Ammonium fluxes into
plant roots: energetics, kinetics and regulation Z. Pflanzen.
Boden. 160 261–8
Glass A D M et al 1999 Inorganic nitrogen absorption by plant
roots: physiology and molecular biology Plant Nutrition
Molecular Biology and Genetics ed G Gissel-Nielsen and
A Jensen (Wageningen: Kluwer) pp 1–16
Min X, Siddiqi M Y, Guy R D, Glass A D M and Kronzucker H J
1999 A comparative study of fluxes and compartmentation of
nitrate and ammonium in early successional tree species
Plant Cell Environ. 22 821–30
Johnson R R, Glass A D M, Kronzucker H J, Gelbart Z, Venczel E,
Paul M, Berkovits D, Cavan A, Kashiv Y and Ghelberg S 1997
Measurement of aluminum transport in wheat at the cellular
level Nucl. Instrum. Methods B 123 283–6
Wang M Y, Glass A, Shaff J E and Kochian L V 1994 Ammonium
uptake by rice roots: III. Electrophysiology Plant Physiol. 104
899–906
Wang M Y, Siddiqi M Y, Ruth T J and Glass A 1993 Ammonium
uptake by rice roots: II. Kinetics of 13 NH+4 Influx across the
plasmalemma Plant Physiol. 103 1259–67
Wang M Y, Siddiqi M Y, Ruth T J and Glass A 1993 Ammonium
uptake by rice roots: I. Fluxes and subcellular distribution of
13
NH+4 Plant Physiol. 103 1249–58
King B J, Siddiqi M Y, Ruth T J, Warner R L and Glass A 1993
Feedback regulation of nitrate influx in barley roots by nitrate,
nitrite, and ammonium Plant Physiol. 102 1279–86
Kronzucker H J, Siddiqi M Y and Glass A 1995 Analysis of 13 NH+4
efflux in spruce roots (a test case for phase identification in
compartmental analysis Plant Physiol. 109 481–90
Kronzucker H J, Glass A D and Yaeesh Siddiqi M 1999 Inhibition
of nitrate uptake by ammonium in barley: analysis of
component fluxes Plant Physiol. 120 283–92
Kronzucker H J, Siddiqi M Y, Glass A D and Kirk G J 1999
Nitrate–ammonium synergism in rice: a subcellular flux
analysis Plant Physiol. 119 1041–6
Kronzucker H J, Kirk G J D, Yaeesh Siddiqi M and Glass A D M
1998 Effects of hypoxia on 13 NH+4 fluxes in rice roots:
kinetics and compartmental analysis Plant Physiol.
116 581–7
Siddiqi M Y, Glass A D M, Ruth T J and Rufty T W 1990 Studies of
the uptake of nitrate in barley: 1. Kinetics of 13 NO3 -influx
Plant Physiol. 93 1426–32
Glass A D M, Siddiqi M Y, Ruth T J and Rufty T W 1990 Studies of
the uptake of nitrate in barley: 2. Energetics Plant Physiol. 93
1585–9
Kafkafi A U, Siddiqi M Y, Ritchie R J, Glass A D M and Ruth T J
1992 Reduction of 13 NO3 influx and 13 N translocation by
tomato and melon varieties after short exposure to Ca2+ and K+
chloride salts J. Plant Nutr. 15 959–75
Glass has used N-13 as a radiotracer extensively over the last
20 years and although the list below is not exhaustive it is
included as evidence of the quality of research that can be
achieved through the use of tracers.
Britto D T, Ruth T J, Lapi S and Kronzucker H J 2004 Cellular and
whole-plant chloride dynamics in barley: insights into
chloride-nitrogen interactions and salinity responses Planta
218 615–22
Britto D T and Kronzucker H J 2003 Trans-stimulation of 13 NH+4
efflux provides evidence for the cytosolic origin of tracer in the
compartmental analysis of barley roots Funct. Plant Biol.
30 1233–8
Kaiser B N, Rawat S R, Siddiqi M Y, Masle J and Glass A D M
2002 Functional analysis of an Arabidopsis T-DNA ‘knockout’
of the high-affinity NH+4 transporter AtAMT1 Plant Physiol.
130 1263–75
Kronzucker H J, Siddiqi M Y, Glass A D M and Britto D T 2003
Root ammonium transport efficiency as a determinant in forest
colonization patterns: a hypothesis Physiol. Plant 117 164–70
Glass A D et al 2002 The regulation of nitrate and ammonium
transport systems in plants J. Exp. Bot. 53 855–64 (Review)
Britto D T and Kronzucker H J 2001 Constancy of nitrogen turnover
kinetics in the plant cell: insights into the integration of
subcellular N fluxes Planta 213 175–81
Britto D T, Glass A D M, Kronzucker H J and Siddiqi M Y 2001
Cytosolic concentrations and transmembrane fluxes of
NH+4 /NH3 : an analysis of a current controversy Plant Physiol.
125 523–6
Kronzucker H J, Britto D T, Davenport R J and Tester M 2001
Ammonium toxicity and the real cost of transport Trends Plant
Sci. 6 335–7
Britto D T, Siddiqi M Y, Glass A D and Kronzucker H J 2001 Futile
transmembrane NH(+)
4 cycling: a cellular hypothesis to explain
ammonium toxicity in plants Proc. Natl Acad. Sci. USA
98 4255–8
Glass A D M et al 2001 Nitrogen transport in plants, with an
emphasis on the regulation of fluxes to match plant demand
J. Plant Nutrition Soil Sci. 164 199–207
Vidmar J J, Zhuo D, Siddiqi M Y, Schjoerring J K, Touraine B and
Glass A D M 2000 Regulation of HvNRT2 expression and
high-affinity nitrate influx in roots of Hordeum vulgare by
ammonium and amino acids Plant Physiol. 123 307–18
Vidmar J J, Zhuo D, Siddiqi M Y and Glass A D M 2000 Isolation
and characterization of HvNRT2.3 and HvNRT2.4, cDNAs
encoding high-affinity nitrate transporters from roots of
Hordeum vulgare Plant Physiol. 122 783–92
Kronzucker H J, Glass A D M, Siddiqi M Y and Kirk G J D 2000
Comparative kinetic analysis of ammonium and nitrate
acquisition by tropical lowland rice: implications for rice
cultivation and yield potential New Phytol. 145 471–6
Min X J, Siddiqi M Y, Guy R D, Glass A D M and Kronzucker H J
2000 A comparative kinetic analysis of nitrate and ammonium
influx in two early-successional tree species of temperate and
boreal forest ecosystems Plant Cell Environ. 23 321–8
Britto D T, Glass A D, Kronzucker H J and Siddiqi M Y 2001
Cytosolic concentrations and transmembrane fluxes of
+/
NH4 NH3 : an evaluation of recent proposals Plant Physiol.
125 523–6
Glass A D M et al 2001 Nitrogen transport in plants, with emphasis
on the regulation of fluxes to match plant demand Pflanzen.
Boden. 164 199–207
Touraine B and Glass A D M 1997 Nitrate and chlorate fluxes in the
chl1-5 mutant of Arabidopsis thaliana: does the CHL1-5 gene
encode a low affinity nitrate transporter? Plant Physiol.
114 137–44
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C-11 as radiotracer
even after proton transport is decoupled Planta
226 541–51
Ferrieri A P, Thorpe M R and Ferrieri R A 2006 Stimulating natural
defenses in poplar clones (OP-367) increases plant metabolism
of carbon tetrachloride Int. J. Phytoremediation 8 233–43
Babst B A, Ferrieri R A, Gray D W, Lerdau M, Schlyer D J,
Schueller M, Thorpe M R and Orians C M 2005 Jasmonic acid
induces rapid changes in carbon transport and partitioning in
Populus New Phytol. 167 63–72
Babst B A, Ferrieri R A, Gray D W, Lerdau M, Schlyer D J,
Schueller M, Thorpe M R and Orians C M 2005 Jasmonic acid
induces rapid changes in carbon transport and partitioning in
Populus New Phytol. 167 63–72
Thorpe M R, Ferrieri A P, Herth M M and Ferrieri R A 2007
(11 C)-imaging: methyl jasmonate moves in both phloem and
xylem, promotes transport of jasmonate, and of photoassimilate
23