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MIC
MIC
MOLECULAR
IMAGING
CENTER,
NIRS
独立行政法人放射線医学総合研究所
http://www.nirs.go.jp/research/division/mic/eng/
National Institute of Radiological Sciences
分子イメージング研究センター
Molecular Imaging Center
MOLECULAR
IMAGING
CENTER, NIRS
National Institute of Radiological Sciences
独立行政法人 放射線医学総合研究所
Molecular Imaging Center
分子イメージング研究センター
4-9-1,Anagawa,Inage-ku,Chiba-shi,263-8555 JAPAN TEL:+81-(0)43-206-4706 FAX:+81-(0)43-206-4079
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Ver.1.0 E 2009.06.11
http://www.nirs.go.jp/research/division/mic/eng/
MIC
National Instisute of Radiological Sciences
MOLECULAR IMAGING CENTER
Contents
Historical Timeline
…03
1957
National Institute of Radiological Sciences (NIRS) was opened.
1974
The first medical cyclotron of Japan was installed.
1976
Diagnosis using radioactive isotope (RI) beams produced by the cyclotron was
made for the first time.(13N, evaluation of liver function)
1977
High-speed positron camera with short-lived RI was successfully developed.
1979
Positron computed tomography (CT) was applied in a clinical setting for the first
time in Japan.
1980
Technology to produce high-volume of compounds labeled with short-lived RI was
developed.
1982
A test model of a whole-body multilayer positron CT machine was completed.
1996
A research station for advanced diagnostic function was established.
2000
High-quality radio-pharmaceutical hot laboratory that is capable of good
manufacturing practice (GMP)-grade production was opened.
2002
The first positron emission tomography-computed tomography (PET-CT) machine
of Japan was installed.
Safety Assurance, Ethics, and Regulatory Sciences
2003
A three-dimensional radio detector for next-generation PET machines was installed.
…11
2004
A 7-Tesla magnetic resonance imaging (MRI) machine was developed.
Historical Timeline
…04
Toward better diagnosis of diseases and
innovations in evaluating therapy
…05
Facilities•Equipments
…06
What is Molecular Imaging?
…07
Molecular Imaging at NIRS
…08
Prominent Molecular Probe Synthesis System
…09
Molecular Probe
…10
Molecular Imaging
…12
Sponsored by the Ministry of Education, Culture,
Sports, Science and Technology, Japan
Organization
A clinical trial to estimate the optimum dosage of a new antidepressant agent was
conducted.
Promotion of Molecular Imaging Research
NIRS was selected as the “Research Base for PET Diagnosis” in the Molecular
Imaging Research Program; it receives a 5-year grant from the Japanese Ministry
of Education, Culture, Sports, Science and Technology. (FY2005–2009)
…14
The Molecular Imaging Center was established.
…13
Diagnostic Imaging Group
…16
Molecular Neuroimaging Group
…18
Molecular Probe Group
…20
Biophysics Group
…22
Vision of the Future
MOLECULAR IMAGING CENTER P2
2005
2006
The Molecular Imaging Center concluded an agreement with Tohoku University for
organizational partnership.
2007
The Molecular Imaging Center concluded an agreement with RIKEN Brain Science
Institute for organizational partnership.
2008
The Molecular Imaging Center concluded a Memorandum of Understanding on
Research Cooperation with Joseph Fourier University, France.
Open PET geometry was proposed for the first time in the world.
The Molecular Imaging Center concluded a Memorandum of Understanding on
Research Cooperation with Trakia University, Bulgaria.
MOLECULAR IMAGING CENTER P3
What is Molecular Imaging?
Molecular Imaging
Molecular imaging is a discipline that enables the
non-invasive visualization of molecular behavior in
the living body. It is a newly emerging field of
study that combines molecular biology
techniques for the investigation of molecular
functions in the living body and the technology for
the visualization of these molecules. The 4
important technologies that have been
established in the field of molecular imaging
comprise PET, SPECT, MRI, and fluorescence
imaging. PET and SPECT are considerably
effective in whole-body imaging of human
subjects; similarly, MRI is effective for imaging
body structures, while fluorescence imaging is
appropriate for the imaging of deeper regions of
the body at cellular and molecular levels. By using
these imaging modalities to take advantage of the
other modalities and to complement each other,
the new and varied applications of molecular
imaging can be developed. The advancement of
molecular imaging is expected to provide us with
improved methods for the determination of the
optimal drug dose, for the elucidation and
diagnosis of diseases and pathological conditions,
for the realization of individually tailored therapy,
and for bringing about drastic improvement in the
structure of the drug-discovery process. In
addition to these prospects of direct and multiple
applications in the clinical field, molecular imaging
can contribute to fundamental investigations to
reveal the secrets of life such as molecular
biological investigations. In particular, as this is the
beginning of the post-genomic era, molecular
imaging plays an important role in the paradigm
shift observed in the field of life sciences in which
its major objectives range from unscrambling the
genetic codes to investigating the functions of
biomolecules.
PET
Positron Emission Tomography
PET is a type of radionuclide scanning that utilizes
trace amounts of radioisotopes. The PET scanning
process involves replacing an element in a molecule
or analogous molecule with a radioisotope, which
emits positrons (i.e. labeling the compound), and
introducing the radiolabeled molecule (i.e. molecular
probe, radiopharmaceutical) into the living subject.
RI in molecular probes emits a positron (e+) when it
undergoes radioactive decay. After traveling a short
distance, the positron encounters and annihilates
with an electron (e-), which is a particle with a
charge opposite to that of a positron, thereby
producing a pair of annihilation (γ) photons moving
in opposite directions. A PET scanner detects these
γ-rays, and images of the body distribution of a
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Molecular Imaging at NIRS
targeted molecular probe are reconstructed using
positional and temporal data.
In PET methodology, it is possible to visualize
various biological reactions occurring in the living
body by designing PET probes in order to detect
targets.
PET image of a case of lung cancer
As shown in the table provided below, the halflives of positron emitting nuclides are so short
that the period of time to which the subjects are
exposed to radiation would be less than that
observed in traditional scanning methods utilized
in the field of nuclear medicine. A reduction in the
radiation exposure also enables repeated
scanning. Another advantage of PET scanning is
its quantitative performance. In addition, the
spatial resolution and sensitivity of PET has been
improved; this can be observed from the fact that
the spatial resolution of the PET machine that is
currently in use is less than 3 mm.
PET utilizes positron emitters such as carbon,
nitrogen, and oxygen. These elements are
structural components of living matter and are
used as test agents (molecular probes) for amino
acid, glucose, water, and oxygen.
Nuclide
Carbon
11
C
Nitrogen
13
N
Oxygen
15
O
Fluorine
18
F
Copper
62
Cu
Rubidium
82
Rb
Half-life
Production method
20 min
Cyclotron
10 min
Cyclotron
2 min
Cyclotron
110 min
Cyclotron
10 min
Generator
75 s
Generator
Major positron-emitting radionuclides
SPECT
Single Photon Emission
Computed Tomography
SPECT is an imaging technique with RI that is
used in the assessment of functions of the living
body and the diagnosis of many diseases and
tumors. RI is utilized in both PET and SPECT;
however, they radiolabel different elements.
SPECT uses γ-ray emitting RIs, whereas PET
uses positron-emitting RIs.
Monoenergetic photons (γ-ray) emitted from the
RI injected in the living body are captured; this
enables physiological functions of the body to be
visualized by tomography.
MRI
Magnetic Resonance Imaging
MRI utilizes a phenomenon called nuclear magnetic
resonance (NMR), in which an atomic nucleus
absorbs resonating energy and subsequently
releases it in the form of electromagnetic rays. MRI
imaging mainly uses protons, which form the
nucleus of hydrogen atoms, as these atoms occur
in the human body in large quantities. Magnetic field
strength distribution is captured as signal intensity
distribution, and sectional images of the subject are
acquired.
MRI is a non-invasive test that does not involve
radiation exposure and provides strong organ
contrast, which enables the differentiation between
benign and malignant tumors as well as the
visualization of blood vessels without the use of
contrast agents. Furthermore, a variety of
information can be acquired from a single location
by altering tomography parameters. The spatial
resolution in MRI is approximately 1 mm, while the
temporal resolution is approximately 1 s.
PET
Human level
MRI
SPECT
Fluorescence imaging
Animal level
Tissue level
Cell level
MRI image of the human brain
Fluorescence Imaging
Fluorescence imaging applies the principles of
both fluorescence and luminescence into practice
to observe 1 specific molecule in cells or
individuals. It enables the determination of the
location and measurement of the quantity of the
molecule. There are 2 prominent fluorescence
imaging techniques: one that involves light
absorption and/or reflection of intrinsic molecules,
and the other that administers extrinsic fluorescent
or luminescent substances. The latter method is
associated with the expression of genes that
encode luminescent proteins and specific
enzymes that can generate luminescent reactions
on substrate injection and on intracellular injection
of fluorescent materials.
By observing fluorescence and luminescence with
an optical microscope, we can visualize molecular
and cellular events within the living body of rats or
mice. Thus, fluorescence imaging is useful for the
analysis of the dynamic state of fluorescencelabeled peptides and proteins in addition to the
local existence of cells and proteins.
Detector
positron
Molecular Biology
Life Science
In addition to the knowledge on the techniques and know-how to enable
bench-to-bedside research, NIRS has been accumulating fundamental
molecular imaging equipments for many years. Now, these resources are
applied to molecular imaging research, which enables the investigation of
molecular/cellular events and dysfunction within the living body. This is
one of the consistently promoted fields of research at the NIRS as “Life
science research involving use of nuclear radiation.”
Considerable knowledge and know-how on the techniques of basic
biological science are essential to successfully perform molecular
imaging research. At NIRS, since it has not yet received recognition as a
core of Molecular Imaging, exploratory research for the discovery of the
causes and therapeutic targets of cancer, higher brain dysfunction,
metabolic disorder, and other diseases has been undertaken for the
purpose of formulation of the basic research grounds of diagnosis and
therapy using nuclear radiation.
The subsequent phase following the identification of candidate targets of
molecular imaging by basic research involves determining the technology
in which these targets can be visualized; this would require the
establishment of techniques for imaging at the cellular and molecular
level first, and the assessment of these targets as diagnostic and
therapeutic targets. Simultaneously, the researchers will be involved in
exploring the possibilities of the applicability of the technique in in vivo
imaging. Generally, optical imaging, MRI, or radiological modalities such
as PET and SPECT are employed for in vivo imaging. It is one of the
strengths of NIRS that it has a comprehensive group of professionals
who understand the characteristics of each of the imaging modalities
and are capable of developing new detectors specialized for each
purpose ready to successfully initiate research.
When the possibility of in vivo imaging has been corroborated, the
subsequent phase involves considering its potential for human
application. It is essential to provide a production system for molecular
probes that are of a quality sufficient for human injection, and provide
evidence for the probe efficiency and give safety assurance. NIRS is the
first research institute in Japan that manufactures PET probes using
facilities, equipments, and systems that conform to GMP standards.
Further, in cooperation with the Research Center for Radiation Protection,
which is the professional group of NIRS that deals with radiation
exposure, the Molecular Imaging Center members are working toward
the realization of safe PET examination.
neutron
SPECT image of tumor
MOLECULAR IMAGING CENTER P6
Fluorescence image of a living mouse
MOLECULAR IMAGING CENTER P7
Prominent Molecular Probe Synthesis System
Molecular Probe
Molecular Probes and Probe Library
Synthesis technology for
Ultra-high specific radioactivity
Stable Production Supply
GMP Standards
At NIRS, greater than 50 kinds of radiopharmaceuticals have been applied to clinical practice, to date.
In the future, the yearly development of 2 or 3 new pharmaceuticals designed for clinical use will continue.
Specific radioactivity is an indicator of the amount of
radiation (Ci, GBq, etc.) in a particular amount
(measured in μmol, μg, etc.) of radiolabeled
compounds. Theoretically, a dose of 1 pmol (10-7
mg of 100 molecular weight) of 11C-labeled
pharmaceuticals, which have a half-life of 20 min, is
required per human subject to perform a PET
examination. However inpractice, these
pharmaceuticals are attenuated by a suite of
carbons in the environment. Accordingly, the only
approximately one-ten thousandth density of the
theoretical value of these pharmaceuticals can be
acquired, and a considerable amount of ligand is
required for their satisfactory isolation. Extremely
advanced techniques are required for the
application of high doses of radiation to labeled
Because of the short half-lives of positron
emitters (e.g. 11C; t1/2 = 20.4 min, 18F; t1/2 =
109.8 min), it is impossible to produce PET
molecular probes in advance and store them
for future use. Therefore, they must be
produced at the location at which they are to
be used upon receiving each request. The
effective conduct of clinical study and research
is dependent upon the kind of PET probes and
the number of times production can be
performed on a daily basis. At NIRS,
automated synthesis devices and production
systems are developed using in-house
expertise, which enables the production and
provision of various PET probes up to 4-6 times,
sometimes even 10 times upon request, per
The NIRS was the first among PET facilities in
the world to recognize the significance of good
manufacturing practice (GMP) and the potential
danger of radiation exposure to personnel and
developed comprehensive intelligent production
system oriented to GMP. We produce a number
of PET molecular probes with high-quality and
safety under a clean fabrication environment.
This system made it possible not only to
automatically produce PET probes, but also to
control the entire production process, from
ordering of probes to the administration to the
subject. Consequently, operators are not
required to come in contact with the probes
(radioactive substances) at all throughout the
entire production process, and the radiation
compounds. NIRS has already established 10- to
100-fold higher specific radioactivity using its
compounds than has been reported around the
world. This technique for the production of “ultrahigh specific radioactivity” developed by NIRS
enables us to conduct various PET tests and
research at a much higher sensitivity than that
achieved in other research institutes. In addition,
the ultra-high specific radioactivity technique can
decrease the amount of compounds to be used
(PET pharmaceuticals) in the tests; therefore, it is
possible to perform imaging even on physiologically
active substances without affecting living organisms.
Likewise, this technique enables the visualization of
molecules that occur at very low concentrations in
the living body. NIRS has already achieved ultrahigh specific radioactivity for the synthesis of 11C,
13N, 18F, and other pharmaceuticals.
day. In fact, we can produce approximately 60
kinds of PET probes for clinical application and
more than 100 probes for basic research,
respectively. These probes are used safely at a
rate of greater than 1,000 times per year. The
technology and skills possessed by our center
for the stable production and supply of PET
probes enables us to meet the various needs of
molecular imaging research.
exposure to the operators is reduced drastically.
Simultaneously, this system provides for the
concept of GMP, which places emphasis on the
prevention of human errors, contamination, and
quality decline of radiopharmaceuticals. The
entire system is capable of performing
complicated procedures automatically with less
human intervention.
Disease-specific radiopharmaceuticals (molecular
probes) are essential for diagnosis using
molecular imaging methodologies, such as PET
or SPECT. Different functions can be visualized by
altering the pharmaceuticals employed. The
number and variety of automated-synthesis
devices used for the production of these
radiopharmaceuticals as well as the production
system differs between institutions. The ready-touse pharmaceuticals produced, therefore, differ
to a considerable extent between institutions.
The MIC at NIRS has been continuing its efforts
to enrich the menus of molecular probes (probe
library). It has enabled the synthesis of molecular
probes—the effectiveness of which has already
been verified by other research institutions—in
addition to developing novel molecular probes
using its in-house expertise. As it possesses the
skills and techniques that are required to produce
these high-quality probes and ensure that their
safety is sufficient for their administration in
human subjects, NIRS can meet diverse
demands being made by the clinical research
sectors.
MIC is currently involved in the expansion of the
probe library, so as to meet the needs of both
internal and external researchers.
Optimal maximum theoretical specific radioactivity
C
11
C
1200
Network
Good manufacturing practice (GMP) concept
800
2.Prevention of contamination and quality decline of pharmaceuticals
3.Establishment of high-quality assurance system
400
0
1994
1996
1998
2000
2002
2004
2006
(FY)
Growth in production
The number of PET radiopharmaceutical production
Production Routine for
Radiopharmaceuticals
System
Database
Automated scheduling
Monitoring and recording
Barcode approval
11
[11C]SCH 14
[11C]RAC 28
[11C]WAY 16
Others 34
[ C]BTA 35
[ C]FLB 41
[11C]DASB 16
C
Other institutions:
NIRS:
approximately
1Ci /μmol
Dosage （10 mCi/time）
NIRS: less than 0.1 nmol
↑
Ordering of
radiopharmaceuticals
Tracking the progress
Diagnosis
Clinical research
11
[ C]DOPA 36
62Zn/Cu Generator 18
[18F]FDG 107
Production of radionuclide
Checking
the preparation list
Automated
Synthesizer
Radiosynthesis,purification,
formulation
[18F]FLT 36
200 Ci /μmol
Cyclotron
[11C]Met 908
Automated
Autoradiographic image of brain slice with [ C]Raclopride
11
Quality check
pH, purity, etc.
Breakdown of pharmaceuticals
125 Ci/μmol 2 Ci/μmol 1 mCi/μmol
The above-provided image shows that the higher the specific activity,
the higher the clarity of the image.
This is an autoradiographic image obtained by applying [11C]Raclopride
that has the same total radioactivity but different specific radioactivity
compared to brain slices obtained from the same rat.
MOLECULAR IMAGING CENTER P8
Flow of Pharmaceutical Production
11
Achieved value of specific radioactivity
Diagnosis of
Disease Conditions
such as Alzheimer’s Disease
OCOCH3
Serotonin 5-HT1A Receptor
[11C]WAY100635
Muscarinic Acetylcholine
Receptor (mAch)
[11C]NMPB, [11C]3NMPB
Opioid Receptor
[11C]Carfentanil
[11C]PAE
Cholinergic Enzyme
Acetylcholinesterase
[11C]MP4A [11C]MP4P [18F]EP4MA
[18F]EP4A
Brain
Butylcholinesterase
[11C]5R3B [11C]MP3B [18F]FEP4MB
Metabotropic Glutamate
[11C]PTBN
Phosphodiesterase
[11C]Rolipram
Glucose Metabolism
Dopamine Metabolism
[11C],[18F] DOPA
[18F]FDG
Tumor
Fat Metabolism
Bone
DNA Synthesis
Receptor
[11C]S-dThd
[18F]Estradiol
[11C]Methionine
[11C],[18F]Tyrosine
[18F]FLT
Blood Flow
[61,62Cu]HSA
[15O]H2O
[13N]NH3
[38K]K+
Circulatory Organ
Protein Synthesis
[18F]NaF
Serotonin
[11C]DASB
[11C]McN5652
Multiple Drug Resistance
Norepinephrine
Protein
11
[18F]FMeNER-d2
[ C]Verapamil
[11C]Oseltamivir
Glial Metabolism
Benzodiazepine Receptor (BZR)
[11C]Ro15-4513
11
Peripheral Benzodiazepine [ C]Flumazenil
Receptor
NMDA-type Glutamate Receptor
[11C]DAA1106
[11C]Ac-L703,717
[18F]FEtDAA1106
[11C]Ac5216
Substance P Receptor
[18F]FEt-SPARQ
At NIRS, PET scanning is performed prior to and following
charged particle therapy as well as for brain function research.
[11C]Met and [18F]FDG are PET probes that are used for tumor
diagnosis, while the others are used for brain function imaging.
FY2007: 1289 subjects, 19 pharmaceuticals
[11C]MP4A
Characterization of
Malignant Tumors
[11C]Choline
Hypoxic Tissue
[61,62Cu]ATSM
[18F]Misonidazole
[11C]Methyl-Kigamaycin
Oxygen
Metabolism
[11C]Acetate
[11C]Iressa
11
CH3
For the purpose of imaging the activities of the
cholinergic nervous system (acetylcholinesterase
activity), [11C]MP4A has been developed.
By quantitatively measuring the acetylcholinesterase
activity, we demonstrated differences among
cholinergic nervous conditions observed in various
cases of dementia. In addition, we succeeded in
elucidating the direct pharmacological effects of
Alzheimer’s disease in the human body. This helps
the discrimination between similar disease
conditions and the adoption of appropriate remedial
measures.
[11C]MP4A is an original probe developed by NIRS;
the development of his probe from molecular
design, labeling, synthesis, and evaluation, to the
analytical method, was conducted at NIRS.
O
11
CH3
HO
S
N
1.Reducing human errors
1 atom
11
Dopamine D2 Receptor
[11C]Raclopride
[11C]FLB457
[11C]NMPA
Dopamine
[11C]PE2I
[11C]BF227
[11C]PIB
Network
FY 2007:1658 times
150 million atoms
Dopamine D1 Receptor
[11C]SCH23390
[11C]NNC112
Transporter
Amyloid
PET probes available at NIRS (as of October 2008)
1600
1992
14
Automated comprehensive
radiopharmaceutical
production system
Neural Receptor
NH
N
Drug Evaluation
O
O
OH
For the purpose of imaging the proliferation of a
malignant tumor, we developed [11C]S-dThd by
using a thymidine derivative .
We performed imaging on C6 tumor-bearing mice
and succeeded in acquiring an image of highproliferation tissues such as the tumor and the
bone marrow. Since the tumor uptake of [11C]SdThd was observed to be significantly high, this
probe is expected to be a potential novel tumor
imaging probe, which can be used with an
effectiveness greater than that observed with
[18F]FLT. This NIRS-developed probe is going to
proceed to clinical research.
Face-down
[11C]Oseltamivir
11
C
CH3
O
NH2
EtO
[11C]S-dThd
H
N
O
For the purpose of investigating the behavior of
R
○
Tamiflu (Oseltamivir)—an influenza drug—in the
brain, we established an effective production
method for it and succeeded in the fully
automated synthesis of [11C]Oseltamivir for the
first time in the world. The success of this
system was realized in the use of the versatile
automated synthesis system.
We utilized an animal PET machine to measure
the uptake of this probe in young and adult
rats, and found that radioactivity concentration
in the brain of the young rats is higher than that
observed in that of adult rats. This molecular
probe helps in revealing the side-effects of
R
○
Tamiflu administration.
Sideways
Brain
Automated
↑
Dispensing
Delivery
-via an automated
transfer system
Normal
Alzheimer’s Disease
[11C]MP4A image of the human brain
[11C]S-dThd image of C6 tumor-bearing mouse
(Tumor on the right shoulder)
Young rat
Adult rat
[11C]Oseltamivir image in the rat brain
MOLECULAR IMAGING CENTER P9
Safety Assurance, Ethics, and Regulatory Sciences
Molecular Imaging
Sponsored by the Ministry of Education, Culture, Sports, Science and Technology, Japan
Research Base for PET Diagnosis
Clinical Trials
Clinical Research
Pharmaceutical Affairs Law and GCP
Ethical guidelines for Clinical Research
(
Standards for the Implementation of Clinical Trials
on Pharmaceutical Products
)
Ethical guidelines for Human Genome and
Genetic Analyses Research
Ethical guidelines for Epidemiological Research, etc.
・Report to the Ministry of Health, Labour, and Welfare
・Approval by the institutional review board
・Permission of the director of the institute
・Informed consent of the subject
・Adverse event reporting to the Ministry of Health,
Labour, and Welfare
・Compensation for injury
・Monitoring and audit
・Investigation by the Ministry of Health, Labour, and
Welfare
・Register research programs in the database of private sectors
・Approval by the ethics committee
・Permission of the director of the institute
・Informed consent of the subject
・Adverse event reporting to the Ministry of Health, Labour, and Welfare
・Compensation for injury
・Education and Training of researchers and ethical committee members
・Investigation by the Ministry of Health, Labour, and Welfare
Microdose Clinical Trials
Managing Conflicts of Interest
・Monitoring radiation exposure in human
subjects and handling of radioisotopes
Guidelines for Conflicts of Interest Management
The Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) launched the “Molecular Imaging Research Program” as one of the
research programs in the field of life sciences that reflect social needs. This program aims to apply PET and other imaging methods to innovate through
drug discovery as well as to promote technological development for diagnosis and therapy evaluation. MEXT publicly sought for “Research Base for
Exploring New Drugs” and ”Research Base for PET Diagnosis,” which are leading research institutes. Consequently, NIRS was adopted as the “Research
Base for PET Diagnosis.”
The Molecular Imaging Center, NIRS, as a Research Base, is destined to promote and develop PET fundamental technology, such as that establishing the
largest molecular probe library of the world and the development of synthesis technology for super-high specific radioactivity, while taking measures to
promote the dissemination of research results. Further, in addition to therapy evaluation methods, we aim at developing diagnostic analysis and diagnostic
modality methods for a variety of diseases.
Molecular Imaging Research Program
Research Base for
PET Diagnosis
Research Base for
Exploring New Drugs
Cooperation
NIRS
RIKEN
・Development of innovative molecular probes
・Development of a synthetic method for
・Labeling molecular probes with ultra-high
Personal Information Protection
molecular probes
・Identification of new drug candidates
specific radioactive isotopes
・Development of an automated synthesis
Laws on protecting personal information that is maintained
by independent administrative institutions and other sectors
system for medium half-life radionuclides
Innovation in Drug Discovery
Innovation in Diagnosis
All Japan-nationwide commitment
Acts, Laws, and Guidelines
Compliance
Safety of Subjects Exposed to
Radiation
Contribution to development of
novel healthcare technology
Among all molecular imaging studies being
conducted, those involving human participants
should be regulated by the laws and ethical norms
to the highest extent in order to assure the safety
of the participants. In Japan, clinical trials
conducted among at new drug application for
marketing authorization are conducted under strict
legal monitoring. Clinical researches conducted
without the intention of new-drug application are
regulated by the guidelines issued by the
Japanese government such as Ethical guidelines
for Clinical Research, Ethical guidelines for Human
Genome and Genetic Analysis Research, and
Ethical guidelines for Epidemiological Research,
and so on. In any types of clinical researches,
approval from the ethical committee and informed
consents of the subjects are required. In addition,
clinical trials aiming at marketing authorization are
required to be registered to the regulatory authority
and have them investigate the trial. Further,
management of the Conflict of Interest (COI) and
the protection of personal information are needed.
In the clinical researches administrating radioisotope
to humans, radiological protection of human
subjects are absolutely necessary. In a “microdose
clinical trial”, extremely small amount of candidate
compound labeled with radioisotopes are
administered to humans and phamacokinetics
/phamacodynamics data of the compound is
obtained. In 2008, Guidelines for the microdose
clinical trial were published in Japan by the Ministry
of Health, Labour, and Welfare. This guideline is the
first to state the policy of the nation with respect to
radiological protection of human subjects.
The National Institute of Radiological Sciences has
established strict monitoring system for radiological
protection of research subjects since decades
before the governmental guideline was issued, then
it has contributed considerably to the compilation of
the guideline. In future, we will collaborate with
greater number of research institutions to develop
research governance framework in view of
radiological protection, learning more from the
international frameworks.
The “Microdose clinical trial” guideline has made a
breakthrough of applying molecular imaging
methodology that utilizes PET and SPECT to new
drug development. From the perspective of the
pharmaceutical industry, new drugs are developed
to a greater extent in foreign countries than in
Japan. This situation is referred to as “hollowingout of the clinical trials” or “drug lag” and has been
considered to be a serious problem. However, the
microdose clinical trial marks a turning point since
the entire process of drug development from the
initial screening to the later approval application
process, can be brought back to Japan. Further,
molecular imaging technology is expected to be
applied with a higher frequency at the later stages
of drug discovery.
Molecular imaging methodology is essential not
only from the aspect of drug discovery but also in
the field of brain imaging studies, which have been
promoted globally. We are involved with the ethical
and social issues related to such cutting-edge
research so as to promote public understanding
science of these field.
MOLECULAR IMAGING CENTER P10
Universities
Research institutes
Pharmaceutical companies
Clinical application
and popularization
Medical device industries
Advancement of science and technology
Promotion of Health on a Nationwide Basis
Fostering of Human Resources and Collaboration with Academia and Business Concerns
Fostering human resources in the research field of molecular imaging is one of the important missions of the NIRS as the Research Base for PET Diagnosis.
NIRS continues to hire postdoctoral fellows and technical staff who are expected to become promised specialists with expert knowledge. In addition, Tohoku
University, which entered into a basic collaboration with NIRS on molecular imaging, started a new graduate program for molecular imaging in FY2006. This
“Molecular Imaging Education Course,” has been effective as a foster program. Currently, several students belonging to the workforce are involved in research
activities at NIRS. Furthermore, the MEXT molecular imaging research program supports collaborative research projects with academic and industrial sectors.
The projects are intended to take advantage to the greatest possible extent of the fundamental technologies and equipments of NIRS, which have been
maintained with the budget of MEXT, and to deliver prospective foresight on the clinical application of PET imaging; the titles of these projects are
“Development of New Molecular Probes Targeting a Cancer Cell-Specific Membrane Protein” (principal site: J-Pharma Co., Ltd.), “Development of Therapeutic
Approaches and Monitoring Technologies toward Tauopathic Dementia (principal site: Kyoto University), and "Development of Diagnostic Methods for
Refractory Tumors including Mesothelioma" (principal site: Juntendo University School of Medicine).
MOLECULAR IMAGING CENTER P11
"Visualize" Cancers
Diagnostic Imaging Group
The Diagnostic Imaging Group conducts research on functional imaging of cancer with
emphasis on positron emission tomography (PET) imaging. During the process of
carcinogenesis and cancer progression, cancer cells acquire various novel characteristics.
If these characteristics can be evaluated by imaging, we can clarify properties of individual
cancers directly related to treatment, such as malignant grade of tumors, sensitivity or
resistance to treatment, and expression of therapeutic target molecules. This could enable
the formulation of therapy plans on the basis of these characteristics and to judge or
predict the effectiveness of therapy from changes in these characteristics by treatment,
and to contribute for the so-called personalized medicine. Although many kinds of PET
probes, such as 18F-fluorodeoxyglucose (FDG), 11C-methionine (Met), 18F-fluorothymidine
(FLT), and Cu-ATSM, have already been developed and clinically applied, it is expected
that development of new probes will be necessary for the more precise characterization of
caners. In our group, in addition to the research on cancer characterization using PET
probes that are already available, we conduct researches associated with the following
areas: (1) exploration of novel targets of tumor imaging, (2) development of radiolabeled
probes to detect new targets, and (3) development of sensitive imaging methods using
functional imaging techniques such as PET. The goal of this Group is to make clinical
contributions in the management of cancer patients, including heavy particle therapy
conducted at the NIRS.
Group Leader: Tsuneo Saga
Clinical Diagnosis
Team
Molecular Diagnosis
Team
Biomolecule
Team
"Diagnose" Cancers
"Portray" Cancers
"Explore" Cancers
The Clinical Diagnosis Team conducts clinical
research on functional imaging methods for
tumors, mainly based around PET, with the aim
of contributing to the cancer treatment including
heavy particle therapy of cancers. By
conducting clinical research using PET probes,
including FDG, a glucose metabolism marker
that is widely used around the world; Met, an
amino-acid metabolism marker; FLT, a cell
proliferation marker; and Cu-ATSM, a marker of
hypoxia that induce resistance to treatment, the
Team is clarifying the functional roles of each
probe to be used as biomarkers. In addition, the
Team is promoting the clinical application of PET
probes being developed at NIRS. By using
various cancer imaging probes, we can clarify
characteristics of cancer that are important for
the treatment planning and monitoring of
treatment, including malignant grade, presence
or absence of therapeutic target expression,
responsiveness to treatment, and so on, and we
are expecting for the contribution for the better
management of cancer patients by cancer
molecular imaging.
The Molecular Diagnosis Team engages in basic
research on the development of imaging methods
using specific molecular markers, focusing on the
design and evaluation of PET molecular probes,
for the visualization of changes in biomolecules
associated with disease, especially tumors, and
the utilization of these methods for diagnosis.
One of the most important factors to be
considered while designing molecular probes is
the biological phenomenon that is chosen as the
target. As we acquire a deeper understanding of
the characteristics of tumor cells, for instance, the
mechanisms of cell carcinogenesis and the
pathways governing metabolism in tumor cells, we
discover new targets for the development of
molecular probes. Another important factor to be
considered is the elucidation of the characteristics
of existing diagnostic products. We bring back
critical findings gained in clinical research to bench
and study them to understand the fundamentals
of real cancer.
In addition, the Team grapples with the
development of imaging methods useful for the
development of new treatment methods, such as
reporter-gene imaging systems.
The Biomolecule Team aims to elucidate and
clarify the functions of molecular targets for
tumor imaging and also enable their imaging.
We believe that non-invasive imaging of tumorassociated molecular targets will contribute to
early tumor detection and treatment planning.
We conduct research by initially performing
functional screening of genes related to tumorcell proliferation and performing proteomic
analysis on the blood of cancer patients and
healthy individuals in the search for molecular
targets. Thereafter, through analyses of the
functions of the target molecules and their
expression in tumors, we investigate their
usefulness as molecular imaging targets.
Moreover, we develop antibody-imaging
methods for target molecules of mesothelioma,
gastrointestinal stromal tumors, and so on. In
addition, we have succeeded in imaging animal
models such as a tumor-cell-transplanted
mouse model and are currently pursuing
improvements for clinical applications.
Autoradiography
A
A
Before treatment
Cu-ATSM
Immediately after treatment
A
B
B
B
C
D
E
GeneX
FDG
Ki67
ACTB
MIP image
3 months after treatment
FLT-PET images of two cases of lung cancer: The whole-body
image of the first case (left) shows increased FDG uptake in the
cancer in the right lung. The panel on the right (second case)
shows the temporal decline in the uptake of FLT in the lesion in
the left lung resulting from treatment.
A: High Cu-ATSM, Low FDG
B: Low Cu-ATSM
High FDG
The distribution of Cu-ATSM in this tumor differs from that of
FDG. This is probably because Cu-ATSM tends to get
concentrated in areas that contain fewer proliferating cells and
blood vessels, and are thus more resistant to treatment.
Protein expression of a new mesothelioma marker candidate
(showing high-level expression in sarcomatoid mesothelioma (C)
and no expression in normal mesothelial cell and other tumors)
Mouse tumor model electroporated with pFHC-RFP
Liver
MRI(T2WI)
62
Cu-ATSM
Case of uterine cervical cancer: Inhomogeneous uptake of 62CuATSM (yellow arrows) is observed in the tumor detected by MRI
(red arrows), indicating heterogeneous nature of tumor hypoxia.
MOLECULAR IMAGING CENTER P 14
(The entire body:
Fluorescence)
(Tumor: T2W MRI)
(Tumor:Fluorescence)
We successfully captured the expression of the ferritin heavy
chain by MRI. This expression phenomenon is expected to be
utilized in developing a reporter for gene therapy.
Imaging with an antibody that recognizes a tumor marker
overexpressed in mesothelioma (tumor indicated by the arrow)
MOLECULAR IMAGING CENTER P15
Molecular Neuroimaging Group
The Molecular Neuroimaging Group focuses on neuropsychiatric disorders, including
schizophrenia, mood disorders, and Alzheimer’
s disease. Our group adopts both basic and
clinical approaches to better understand pathological conditions and to develop methods for
earlier diagnosis and more effective treatment strategies. Positron emission tomography (PET) and
magnetic resonance imaging (MRI) are used for research with both animal models and humans,
contributing to the development of novel drugs and treatment methods by establishing molecular
parameters and imaging biomarkers for neuropsychiatric disorders.
Group Leader: Tetsuya Suhara
Molecular Neurobiology
Team
System Neurochemistry
Team
Clinical Research for
Neuropsychiatric disease
Molecular Approach to
Living Models
Molecules Connecting Functions
The Clinical Neuroimaging Team is conducting
clinical studies on neuropsychiatric diseases
including dementia, depression, schizophrenia, etc.,
using PET and MRI in order to elucidate their
pathophysiology and develop methods for their early
diagnosis and treatment evaluation.
PET is a tool to quantitatively image in vivo functions
of central nervous system, e.g., neuroreceptor
functions, using various radiopharmaceuticals. Using
this tool, the Team is aiming to understand the
pathophysiology of psychiatric and neurological
diseases in an integrated manner in conjunction with
brain functions and anatomical information obtained
from MRI.
Our research focuses on providing clarification on the
kinetics of radiotracer in the brain, the establishment
of quantitative measurement and imaging methods,
construction of a central nervous function database
using PET, and study the relationship between such
data and brain function information obtained from
MRI. On the basis of these activities, we are
attempting the elucidation of the pathophysiology of
psychiatric and neurological diseases by PET
measurements on the central nervous functions. We
are also utilizing PET technique to evaluate the
therapeutic effects of psychotropic drugs, i.e., to
investigate mechanisms of pharmacological action
and to determine optimum dose for clinical practice.
Neurological diseases are causally linked to core
pathologies exemplified by the accumulation of
proteinaceous aggregates, which trigger a
cascade of molecular and cellular abnormalities
leading to aberrant neurotransmissions and
consequent symptomatic manifestations. Using
PET and other cutting-edge imaging techniques,
we conduct exhaustive in vivo monitoring of
genetically engineered mice that model the 2
hallmark fibrillar lesions in Alzheimer’s disease,
senile plaques and neurofibrillary tangles, and
this approach enables the pursuit of the
cascade from the fibrillogenesis to disordered
neurotransmissions.
Our Team was the first to successfully visualize
senile plaques in mouse models by PET. This
technology is now applied to the development
of new diagnostic and therapeutic agents
targeting the Alzheimer’s disease pathogenesis.
In addition, the Team is dedicated to elucidate
the molecular basis of protective and aggressive
roles played by the neuroimmune system in
diverse neurological conditions, with the aim of
therapeutically regulating neuropathologies. Our
small-animal imaging research is also focusing
on the molecular etiology of psychiatric diseases
by reversely tracing the cascade from
phenotypic and functional alterations to
pathological culprits.
The interactions between heredity and the
environment are a critical factor for the acquisition
of higher brain functioning as well as the related
psychiatric or neurological disorders. In essence,
the development of treatment drugs and
methods should be conducted in line with our
understanding of the conditions surrounding the
disease and the operating principles of brain
function. It becomes possible to accelerate the
advancement of the medical and pharmaceutical
sciences by comparing primate models with
humans and patients since the brain of a primate
has a structure homologous to that of a human
being and is highly differentiated. We elucidate
the processes of brain function maturation and
pathophysiological processes by studying
primate models in terms of "where (localization
and sites of action)," "how (mechanism of
molecular action)," and "what (symptoms and
effects of function)." Using PET, which can
monitor the living brain as a whole, as our main
tool, we achieve an unified understanding of brain
function on the molecular, neuronal, synaptic,
and system levels in order to propose objective
methods of diagnosis and innovative methods of
treatment.
Dopamine D2 receptor Occupancy (%)
Figure of Brain, Shape of Mind
Clinical Neuroimaging
Team
・Vehicle
100
・Aβantibody
Dopamine D2 receptor
Serotonintransporter
[11C]FLB457-PET
[11C]DASB-PET
80
・Amyloid
70
60
Side-effect
No side-effect
40
Optimum dose
6∼9mg/day
20
0
0
5
10
15
Dosage (mg/day)
20
Dose-receptor occupancy curve for the sustained-release
antipsychotic agent paliperidone measured by PET. The optimal
dose of the drug was identified.
・Activated glia
・Senile plaque model mouse 1 week after vaccination
Mouse PET images after vaccine therapy. The side injected with
antibody exhibits activation of immunocompetent glial cells and a
greater reduction in senile plaques than the side injected with the
carrier solvent.
Normal mouse
Tau tg mouse
PET
Marmoset coronal PET images showing the distribution of
dopamine D2 receptors and serotonin transporters.
・Brain permeability
Where (Localization)
・Selectivity
How (Mechanisms)
What
(Effects)
Autoradiography
Treatment
Deposition of amyloid in mild cognitive disorder. Amyloid
deposition is observed in the parietal cortex.
MOLECULAR IMAGING CENTER P16
Activation of glial cells in a mouse model of neurofibrilary tangle
formation (tau Tg mouse; right panels) relative to a wild-type
control (left panels). Atrophy of the hippocampus (encompassed
by dotted lines) is consequent to the neural death.
Understand clinical conditions
PET is useful for investigating the sites and modes of action and
the efficacy of centrally acting drugs within living subjects and is
expected to contribute to drug discovery.
MOLECULAR IMAGING CENTER P17
"Investigate" Molecules with Molecules
Molecular Probe Group
The Molecular Probe Group conducts research on the molecular probes that are
essential for molecular imaging with PET. In the group, we specifically focus on the
development of probes using in-house expertise: the probes under development target
the evaluation of oxidative stress, which is suspected to contribute to various diseases,
as well as evaluation of tumor malignancy and the assessment of both tumor
characteristics and drug-efflux transporter functions. In addition to short half-life nuclides,
we develop and produce medium half-life nuclides such as 76Br and 124I, and metal
nuclides such as 61,64Cu, 63Zn, 62Zn/62Cu generator. Further, in order to develop molecular
probes efficiently, we investigate novel labeling techniques and rapid synthesis methods,
improve useful reaction intermediates, conduct research into labeling techniques with
theoretical specific activity through mass separation, and develop novel apparatus for
the synthesis of molecular probes. Currently, we are focusing on strengthening these
fundamental techniques and facilities to provide a foundation for the Molecular Imaging
Research Program, applying molecular probes that are efficient for imaging of bodily
functions, and expanding the list of probes. The probes already developed are produced
under a production facility system adhering to good manufacturing practice (GMP)
standards and constantly delivered to other research groups and the Research Center
for Charged Particle Therapy Hospital. Further, these achievements are intended to be
used as a molecular probe library by a wide range of researchers from both outside and
inside the country. We are now dedicated to applying these achievements for the benefit
of society.
Group Leader: Toshimitsu Fukumura
Radiochemistry
Team
Probe Research
Team
"Illuminate" Molecules
"Create" Molecules
The main mission of the Radiochemistry Team is pursuing research and
development for the efficient production of diverse and high-quality
molecular probes through the design of new labeling reactions and
developing new methods of synthesis for high-specific activity and
radiochemical yield. One novel synthesis method produced and developed
by the Team has been a PET ligand with a [18F] fluorobenzene ring formed
by the reaction of [18F] F- with a newly labeled precursor diphenyliodonium
salt with various substituents in its benzene rings. We established a
production method for the labeled intermediates [11C] nitromethane, [11C]
methyl chloride, etc. with a stable and reproducible yield, and developed
new labeling reactions using these molecules for application in probe
development and production. Further, in addition to existing PET ligands,
we are producing probes with high specific activity, using labeled
intermediates of ultra-high specific activity. Using these probes, we have
visualized bindings not previously observed in tests using probes with
normal specific activity.
For the development and advancement of molecular imaging, the creation
of excellent probes is essential. The Probe Research Team either invents or
selects measurement principles for the accurate capture of targeted vital
functions and molecules and designs molecular probes. Probes are then
developed in the same manner as new drugs, by evaluation and
verification in animals and humans on the basis of defined measurement
principles. By assuming a kinetic strategy that especially utilizes
metabolism, the team has developed uniquely creative and excellent
probes; these probes are clearly distinct from the probes developed by
other research institutes. This active employment of metabolism enables
both measurements of metabolic rate and the tracking of metabolite
kinetics. In developing this strategy, we also promote the accumulation and
establishment of a theoretical basis for kinetics in probe design. Currently,
measurements of stress conditions and defensive function against foreign
materials, both of which are located upstream of many causes of disease,
are desired, and we are developing probes that quantitatively capture the
biomolecules playing roles in these processes. Examples of such probes
recently developed by our group are provided below.
Radionuclide,
Fluorescent group,
etc.
b
18
CH 3
R1
R2
N
N
N
11
N
H 3 11C
NH
HO
N
N
O
d
c
Br
Radioactive nuclide
Labeled intermediate
Labeling reaction
High-specific radioactivity
Precursor
OCOCH 3
a
14
CH 3
FH2 C
N
O
S
OH
Radioactive probes recently developed:
a: Cerebral acetylcholine esterase, b: Drug efflux pump (MRP1),
c: Oxidative stress, d: DNA synthesis capacity
Molecular probe
Radiopharmaceutical Production
Team
Production System
Team
Produce Safe Molecules
Produce Molecules Safely
In order to apply PET molecular probes to clinical applications, it is
important to establish satisfactory regular production procedures for the
safe administration into human subjects. The Radiopharmaceutical
Production Team regularly produces a wide variety of PET probes used in
clinical molecular diagnoses, such as cancer, central nervous system
disorders and also for basic researches and cooperates with other
teams/groups in (1) development of production methods for the
continuous production of probes with high radioactivity/specific
radioactivity and efficient purity, (2) establishment of fast and reliable quality
control methods to ensure adequate quality of PET probe, (3) evaluation of
toxicity and safety of molecular probes using acute toxicity and other tests,
and (4) estimation of human radiation-absorbed dose from biodistribution
data in animals. Moreover, the Team is conducting contract analyses of
several PET probes including [18F]FDG preparations produced in greater
than 80 PET facilities in Japan, which contributes to the safety use of PET
probe throughout the country.
The Production System Team develops automatic synthesis systems and
other production systems for PET molecular probes for use in molecular
imaging. The production of PET probes is not performed manually but
remotely using automated synthesis systems to avoid radioactive exposure
to the individuals and professionals handling these operations due to the
large volumes of radioactive materials that are essentially used in the early
stages of probe production because of the short half-life of radionuclides.
The NIRS divides this apparatus into units and develops universal multipurpose systems of producing various molecular probes by interchanging
these units as well as new units for the synthesis of various drug agents.
Furthermore, the Team has developed vertical irradiation system for the
production of 124I, 76Br, and 64Cu, necessary for the development of
molecular probes with medium half-life radionuclides. Currently, the Team is
developing technologies for the removal, separation, and refinement of
irradiated targets and production systems for molecular probes with medium
half-life radionuclides.
GMP oriented automated production system for the production of PET radiopharmaceuticals (see P.8)
Radionuclide production
Automated radiosynthesis
Automated quality control testing
Automated dispensing
PET study
Schematic diagram of PET radio-pharmaceutical production
In order to reduce human errors and operator exposure to radiation, the production is under
system control.
MOLECULAR IMAGING CENTER P18
Various drug agents are synthesized within a single system by incorporating a synthesis unit
(right) into a multi-purpose system body (left).
MOLECULAR IMAGING CENTER P19
Magnetic Resonance Molecular Imaging
Team
Biosignal Physiology
Team
"Track" Signals
"Understand" Signals
The Magnetic Resonance Molecular Imaging Team conducts research into
imaging living cells and molecular activity contributing to the
discovery/treatment of diseases and drug development. By combining
high-magnetic field MRI with fluorescent and radiation imaging techniques,
the Team develops new cellular and molecular imaging methods for
research in animals, from mice to primates, and in a wide range of fields
including oncology, neuroscience and regenerative medicine. Examples of
such efforts are the development of a contrast medium that can detect
cellular and molecular activity with high precision and resolution, and also
the development of drug delivery system (DDS) technology that can
simultaneously discover and initiate treatment of a disease. With this
fundamental research, the Team is striving to develop “patient-friendly”
imaging that promotes the early detection and treatment of diseases.
"Measure" Signals
Biophysics Group
The Biophysics Group develops methods for imaging molecular behavior in the living
body, that is invisible to the naked eye. High-sensitivity positron emission tomography
(PET), high-resolution magnetic resonance imaging (MRI), and widely informative
fluorometry measurement are the techniques effective for imaging molecules. Specifically,
PET can investigate body function and dysfunction through molecular behavior after
injecting various radioisotope-labeled molecules and measuring their kinetics in the living
body. Furthermore, PET is so sensitive that it can detect radioisotopes even when they
exist in concentrations as low as 10–9 M. One of the strengths of MRI is its high
resolution, but its detection sensitivity is not as good as PET. In the Biophysics Group,
we also conduct developmental research on the imaging of drug delivery systems (DDS).
A DDS method utilizes probes made of nanoparticles labeled with fluorescent and
magnetic substances so that their access to the target tissue can be assayed by
fluorescence and their location can be determined by MRI imaging. The group includes
four research teams: imaging physics, which develops the fundamental PET technology;
multi-modal imaging methods, which combines MRI and fluorescent imaging; biosignal
functional fusion, which aims to illustrate the relationship between molecular function and
tissue function; and image analysis methods, which quantitatively analyzes bodily
function from PET or MRI images. These research teams collaborate to promote the
development of techniques for imaging the diagnostic biomarkers and therapyevaluation biomarkers for various diseases.
Group Leader: Iwao Kanno
Sub Group Leader: Hiroo Ikehira
The name of our Team originates from our goal of combining imaging
signals obtained from imaging techniques with molecular functions. Our
research activities are roughly divided into 3 categories, namely,
fundamental research, development, and clinical application. In
“fundamental research,” activities consist of attempts to elucidate the
mechanism of functional MRI using fluorescent microscopy and other
techniques. For “development” activities, we are searching for a new
measurement method to replace conventional functional MRI. For example,
we are attempting to develop a novel functional MRI that conducts selective
MRI measurements of the water surrounding nerve cells, in which diffusion
is restricted. In “clinical application” activities, we apply various leadingedge MRI technologies into clinical practice, including MR spectroscopy,
diffusion MRI, and MR elastography (hardness measurement). Through a
close combination of these research activities, from molecules to tissues,
from experimental animals to humans, and from basic research to clinical
application, we are advancing translational research.
Sensitized microscopic MRI of the brain (left)
Quantum dot contrast medium capable of fluorescent and MRI imaging (middle)
Adhesion to tumor cell (right)
(Left) Time-lapse image of cerebral
microcirculation (Green: FITC-labeled red
blood cell, Red: fluorescently labeled blood
plasma with Qdot 605 PEG), visualized with
in vivo two-photon microscopy.
Image Analysis Team
Imaging Physics Team
"Read" Signals
"Detect" Signals
The Image Analysis Team conducts research and development into
methods and algorithms for quantitative molecular imaging with PET. PET
scanning produces images of the distribution of an administered
radioactive drug within the body. However, in molecular imaging of
neuroreceptor concentration, for example, it is necessary to
computationally abstract the radioactivity originating in the drug specifically
bound to the target receptor from measured PET images. The Image
Analysis Team is promoting the development of high-speed and highly
reliable algorithms for this purpose. Although rodents are commonly used
in experimental imaging, this is not always easy due to their small size.
Therefore, we are also developing and validating a system for withdrawing
microvolumes of blood and measuring its radioactive concentration and
the imaging protocols which use this system. From these achievements, it
will be possible to obtain greater amounts of molecular signal information
with greater accuracy.
The Imaging Physics Team has succeeded in developing a high accuracy 3-D
position-sensitive radiation detector for PET (depth of interaction (DOI) detector),
the first of its type in the world. Through the experimental use of this DOI
detector, we produced the high-sensitive, high-resolution PET machine, namely,
jPET-D4, leading to our proposal for OpenPET geometry. We are presently
conducting various kinds of fundamental research into improving the quality of
diagnosis and treatment using OpenPET geometry, integrating PET machines
with other apparatus including diagnostic and treatment devices. This includes
developmental research into new radiation sources and measurement
methods to increase the precision of performance measurements
accompanying the increased performance of PET machines, research into
methods to improve images using radiation information gained from 3-D
position sensitive radiation detectors, research into the development of
detectors that make use of new light receiving elements in OpenPET, research
into measuring time-of-flight γ-rays for improving PET image quality, research
on OpenPET detector configuration and image reconstruction methods, and
research into methods for utilizing OpenPET technology in medical therapy.
count [Bq/ml]
The most sensitive area is opened
x10 4
4
2
0
30
60
The field of view
time after administration [min]
Temporal change of [11C] raclopride (RAC) concentration in the corpus striatum and the
occipital lobe, containing high and low numbers of D2 receptors of RAC, respectively. The
change in concentration differs depending on the concentration of receptors. Appropriate
analysis enables quantification of receptor concentration.
MOLECULAR IMAGING CENTER P20
(Right) A diffusion tensor MR image of a prostate indicating
irregular water diffusion in the tumor region (brown irregular
circle) and oval shape of benign hyperplasia (red circles)
(Joint research: National Institute of Radiological Sciences
Hospital and Chiba University)
Eight-layer 3-D position sensitive
radiation detector (DOI detector)
The field of view is extended
Schematic diagram of OpenPET apparatus
MOLECULAR IMAGING CENTER P21
Multiprobe
Disease diagnosis of the entire body
Dynamic scan
Diagnose
Disease A
Disease B
Disease C
Disease D
Therapy and evaluation of disease
Vision of the Future
Molecular imaging, which directly visualizes the molecular
functions or dysfunctions in the living body, can diagnose
various diseases at the molecular level by imaging the functions
of the healthy humans or the conditions of disease with the use
of various molecular probes non-invasively. Current molecular
imaging methods are limited by the number of diseases that
can be diagnosed using a particular probe. However, in the
future, for instance, in 20 years, an era is expected to arrive in
which multiprobes or hybrid probes that have many functions
and the apparatus that simultaneously images these multiple
information streams have been developed. Then a single
injection may enable the diagnosis, treatment, and evaluation
of various diseases.
Diagnostic Imaging
Group
Molecular Neuroimaging
Group
Molecular Probe
Group
Biophysics
Group
"Shoot" the Cancer
"Examine" the State of Mind "Develop" Molecules
"Navigate" Molecules
The advancement of tumor imaging research is expected to enable us
to evaluate various characteristics of cancer cells in the living body of
model animal or even humans. Information that directly related to cancer
treatment such as tumor malignancy, the probability of
metastasis/relapse, and the information on the presence/absence of the
target molecules for molecular-targeted therapy is essential for choosing
an appropriate therapeutic strategies and also leads to the improved
prognosis of cancer patients. In addition, by imaging the processes
related to carcinogenesis, it may possibly lead to super-early or
preclinical diagnosis and even to the prevention of carcinogenesis.
Furthermore, by labeling probes with cytotoxic radioisotopes such as
β-ray and α-ray emitters, cancer-specific treatment of the whole body
(internal radiation therapy) will be possible. It is highly expected that
molecular imaging will contribute to diagnosis, therapy, and prophylaxis
of cancer to a great extent.
In the near future, a number of imaging biomarkers for schizophrenic
disorder, depression, and Alzheimer’s disease, for which prophylaxis and
treatment are still difficult, will be identified. Further, in the case of
treatment after onset, it will become possible to judge objectively how
effective the treatment is by observing the behavior of these biomarkers;
simultaneously, it is believed that the evaluation of novel therapy
methods will be accelerated. Furthermore, research into the behavior of
the mind will be promoted, and the complex mechanisms governing the
functioning of the brain, which breeds the mind, will be at least partly
untangled. Such mechanisms will be imaged, and it may become
possible to visually confirm the health status of the mind.
Since clinical research with PET first began, tracers to identify the
functions of various targets have been sought. However, to date, no
tracer has been developed that surpasses [18F] FDG. As molecular
imaging depends on the characteristics of molecular probes, in 20
years from now, it is probable that the development of molecular
probes will still be continuing actively. In addition, novel probes to
measure various functions such as the expression of a gene will be
developed. On the other hand, automation of the production of
probes and operations with a risk of radiation exposure will be
promoted further, and this may be achieved using robots in an
unmanned clean room in the future.
Thirty years ago, when radioisotope tomography was first realized, it
took as long as an hour to obtain an image that had a resolution of a
few centimeters at best. Currently, an image with a resolution of a few
millimeters can be obtained with only a few minutes of measuring time.
Will it be possible to develop a radioisotope imaging method that has a
field-of-view as broad as the entire body and that can conduct
molecular imaging at the micro level? Currently, this is possible only by
examination with microscopes invasively targeting the micro level. In the
future, we expect that these examinations will be conducted noninvasively using molecular technology. In other words, probes that we
can currently only dream of, and measuring apparatuses with high
sensitivity, high resolution, and multiple functions will be developed.
MOLECULAR IMAGING CENTER P22
MOLECULAR IMAGING CENTER P23