Download Part 1 - Canadian Association of Nuclear Medicine

Expanding PET beyond FDG
John Wilson
Edmonton PET Centre
Cross Cancer Institute
Edmonton, Alberta
CANM Halifax 2016
18F-FDG
dominates PET nuclear medicine
•FDG is routinely available in major centers.
•FDG accounts for over 90% of PET scans in current clinical
practice
FDG-PET has many strengths but also limitations.
uptake of 18F-FDG in metabolically active tissues
(e.g. brain) makes tumors in or near these structures hard to
evaluate.
• Excretion complicates imaging on or near the bladder and
prostate.
• Tumors with high differentiation and low growth rate can be
difficult to evaluate (prostate tumors and neuroendocrine
malignancies).
• Infected and inflammatory tissues take up FDG.
• Normal
FDG-PET has many strengths but also limitations.
There are many other metabolic and biochemical questions
that are not answered by FDG. (receptor status, protein
synthesis, DNA synthesis etc.).
Hundreds of non-FDG PET radiopharmaceuticals have been
investigated and developed to address these limitations.
Talk Outline
•
Overview of the current regulatory status of PET Radiopharmaceuticals (PERs)
•
Provide an brief overview of a number of non-FDG PERs looking various
molecular targets
– Cyclotron Produced Radionuclides
•
•
•
•
•
•
Skeletal Abnormalities
Phospholipid synthesis
Protein synthesis
Proliferation / DNA synthesis
Cellular oxygenation / hypoxia
Amine decarboxylation.
– Generator produced
11C, 18F
18F-Sodium
Fluoride
11C-choline, 18F-choline
11C-methionine, 18F-Fluoroethyltyrosine
18F-FLT
18F-FAZA
18F-FDOPA
82Rb, 68Ga
• Myochondrial Profusion Agents
• Somatostatin receptors
82Rb
Chloride
68Ga-Dotatate
PET Radiopharmaceuticals as Molecular Imaging Probes
Barriers / Challenges to routine utilization of PET tracers
In Canada, the list is even smaller with only [18F]FDG and the 82Rb-generator to
receive Health Canada NDS approval.
All other Positron Emitting Radiopharmaceuticals (PERs) are used under Clinical
Trial Applications (CTAs)
So while [18F]FDG is widely available as a commercial product, other molecular
imaging agents are available only at PET centres and under restricted protocols
matching the CTA guidelines.
Barriers / Challenges to routine utilization of PET tracers
Canadian Agency for Drugs and Technologies in Health 2015
Compare 99mTc:
There are ~20 99mTc radiopharmaceuticals commercially available to
service the installed base of gamma and SPECT cameras
Source of Major Positron Emitters Used in Nuclear
Medicine
Radionuclide
Half life
Reaction
Production
Method
Carbon-11
20 min
14N(p,α)11C
Cyclotron
Fluorine-18
110 min
18O(p,n)18F
Cyclotron
Rubidium-82
76 sec
82Sr
Generator
decay
(electron capture)
Gallium 68
68 min
68Ge
decay
(electron capture)
Generator
[18F] Sodium Fluoride (Na+F-)
•
Excellent bone imaging agent
•
First introduced in 1962 but was replaced by
99mTcMDP in 1975 due to the wide spread
availability and lower cost of 99mTc .
•
[18F]NaF demonstrates a high sensitivity for the
evaluation of skeleton abnormalities.
•
Early detection of increased bone formation
through interaction with hydroxyapatite, which
constitutes 70% of bone mass.
•
[18F]NaF received FDA approval in 2011 for bone
imaging.
[18F] NaF Pharmacology
•
As with 99mTcMDP, the uptake of [18F]NaF reflects regional blood flow and bone
remodelling.
•
Fluoride ions diffuse through the capillaries and into the extracellular fluid of the
bone and exchange with hydroxyl groups on the surface of hydroxyapatite crystals
to form fluorapatite.
•
The current clinical use of [18F]NaF is for the detection and evaluation of metastatic
bone disease.
– The uptake in metastases is significantly higher than normal bone
•
[18F]NaF does not bind to plasma proteins and is rapidly cleared from the blood and
through the kidneys.
Fig. 3. Fluoride PET is more sensitive than MDP bone scintigraphy. Comparison of
fluoride PET MIP image (A) versus MDP bone scintigraphy (B) in a patient with
metastatic prostate cancer. PET demonstrates more focal lesions than planar
imaging.
Bone, Volume 50, Issue 1, 2012, 128–139
18F
Sodium Fluoride (Na+F-)
• Ease of Synthesis
–
18O(p,n)18F
reaction on H218O water target
– Trap the [18F]fluoride ions on a QMA cartridge
– Elute into the product vial with Sterile Saline
• High yield
• Easy to automate
– Any Automated Synthesis Unit (ASU) for FDG production can be used.
• High potential for distribution off-site
• NaF scans were fast tracked by HC during the Isotope shortage of 20092010.
Barriers
– Installed camera base for SPECT is ~900 across Canada whereas there
are only 47 PET cameras.
– Cost of PET scan much higher than SPECT scan
[11C] Carbon
11C
Carbon is produced by a cyclotron typically via a 14N(p,α)14C reaction.
Specific Characteristics :
Radionuclide
[11C] Carbon
[18F]Fluoride
Half Life
20.4 min
109.7 min
Max positron
energy
970 KeV
640 KeV
Max range in
water
4.1 mm
2.5 mm
Proton bombardment of a gas target of:
99% N2 /1% O2 yields 11CO2
90% N2 /10% H2 yields 11CH4
11C
Methyl Additions
11C
Radiopharmaceuticals
• Wide spectrum of easily accessible PERs
• Body cannot distinguish isotopes so that 11C Radiopharmaceuticals are
equivalent to native compounds
• Reduces the regulatory burden
However:
•
20 minute half life of 11C limits use to facilities with an on-site cyclotron
• Offers potential to study molecular imaging pathway of RP with 11C prior
to modification to an 18F bioisostere for clinical application.
18F
for 11C substitution
• Transporters and some enzymes will tolerate small structural
alterations in endogenous molecules as seen with FDG
• The F for OH or H substitution is termed bioisosterism.
• As observed with FDG, some bioisosteres may have enhanced
molecular imaging properties relative to their endogenous partners.
[11C]-Choline
[11C]Choline is a small molecule that when injected intravenously, is quickly integrated
into the cell membrane as phosphatidylcholine and is a marker of membrane metabolism.
[11C]-Choline
In cancer cells there is an increase in choline kinase activity and a consequent increase in the production
of phosphorylcholine and phosphatidylcholine.
•Biosynthesis of cell membranes represents the rate of tumor cell replication.
•11C Choline has rapid blood clearance allowing imaging to occur within 5 minutes of administration
compared with an hour for 18F FDG.
•11C Choline uptake very low in normal tissues of cerebral cortex, lung, heart, bone and skeletal muscle
allowing for excellent tumor to normal tissue differentiation.
•Unlike FDG, high affinity for malignant prostate tissue including low grade tumors
•Useful for brain and esophageal carcinomas where high background activity of FDG limits detection of
neoplasms.
Clinical Radiology 65, 536, (2010)
[11C]-Choline
11C-Choline
18F-FDG
Fifty-five-year-old patient with increasing PSA level (1.43 μg/l), 27 months after radical
prostatectomy (Gleason score 8). Coronal (left), axial (middle), and sagittal (right) fused image
projections of PET/CT scans. Focal 11C-choline uptake (a) in right (bold arrow) and left (thin
arrow) iliac region revealed lymph node involvement, not observed with 18F-FDG PET (b).
253 × 190 mm (96 × 96 DPI).
Mole Imaging Biol., 12,
210-217 (2010)
18F
MethylCholine
(FCH)
DeGrado et al., J Nucl Med 42, 1805 (2001)
• The usefulness of 11C Choline prompted the investigation of 18F analogues.
• FCH accumulation in PC-3 cancer cells very similar to 11C Choline
• FCH phosphorylation by choline-kinase closely mimics that of choline.
– The phosphorylation step is thought to be crucial for PET imaging because of
metabolic retention of the tracer within the tumor.
•
11C-
and 18F-labelled choline are both rapidly cleared up after injection.
• Very high T/N ratio for both.
• Clinical indications are the same for FCH and 11C Choline making this an
attractive longer lived alternate.
Spine metastases in prostate cancer: comparison of technetium‐99m‐MDP whole‐body bone
scintigraphy, [18F]choline positron emission tomography(PET)/computed tomography (CT) and
[18F]NaF PET/CT
99mTcMDP
[18F]NaF
[18F]NaF
[18F] FCH
(A) Whole‐body bone scintigraphy (WBS) images. (B) [18F]‐sodium fluoride (NAF)‐positron emission
tomography (PET) images. (C) NAF PET/CT images. (D) [18F]‐fluoromethylcholine (FCH)‐PET/CT. The
detection of bone lesions appear to be similar between the two PET/CT scans; however, when looking at
the anterior part of third lumbar vertebra, we find a benign degeneration. On FCH‐PET/CT the benign
lesion does not appear as a hot spot, whereas it does on NAF‐PET/CT.
BJU International, 114, 818 (2014)
L-[methyl-11C]-methionine
11C-MET
11
CH3
S
H
O
OH
NH2
•Measures metabolic demand for amino acids in cancer cells.
•11C-MET uptake is minimal in normal brain providing high contrast for brain tumor
imaging.
•Superior to FDG in brain tumors since the brain has high uptake of FDG as glucose is
the main metabolic substrate. Small malignant lesions are very difficult to detect with
FDG due the high background.
Shown to be useful in monitoring tumor response to treatment in low grade and
recurrent gliomas.
Clin. Nuc. Med. 37, 158-163 (2012)
L-[methyl-11C]-methionine
MRI
11C-MET
FDG
A patient with a suspected relapse of glioblastoma at MRI (a). This finding was
stable for 5 months.
11C-methionine PET (B) was positive, indicating a relapse.
18F-FDG (C) was also positive but the contrast resolution was inferior to that of
methionine PET.
J Nuc Med, 39, 778 (1998)
O-2-[18F]-fluoroethyl-L-tyrosine
([18F]-FET)
Amino acid Analogue
Wester et al., J Nucl. Med., 40, 205, (1999).
High correlation found between MET and FET uptake in brain tumors resulting in
similar image contrast.
No accumulation of activity in normal tissue.
High chemical yields in the synthesis, automation of the synthesis and the longer
half life of F-18 relative to C-11 are advantages over other C-11 and F-18 amino
acid analogs.
Widely used in Europe to study amino acid transport and protein synthesis
O-(2-[18F]fluoroethyl)-L-tyrosine uptake in a recurrent astrocytoma.
Anaplastic Astrocytoma WHO Grade III. T1-weighted MRI after application
of Gd-DTPA (left) and T2 weighted MRI shows widespread abnormalities
but does not allow a delineation of the tumor. FET PET (right) clearly depicts
the tumor while glucose metabolism (FDG PET) is decreased in the tumor
area.
Forschungszentrum Jülich
O
3’-deoxy-3’-[18F]-fluorothymidine (18F-FLT)
O
N
O
HO
Analog of thymidine but does not undergo rapid in vivo
degradation noted with 11C-thymidine and has a longer
radionuclide half-life.
CH3
HN
18
F
Substrate for nucleoside transporter and substrate for thymidine kinase.
Phosphorylated compound appears to be stable and is not able to leave the cell providing
metabolic trapping.
Is not taken up in DNA but acts as an indicator of cell proliferation through involvement
in the thymidine salvage pathway.
Stable in plasma and low level of glycolytic cleavage.
Early indication of general application as an indicator of cellular proliferation (marrow)
and tumor growth.
PET Image Enhancement
• Metabolism vs Proliferation
FDG
FLT
J Nucl Med 2005; 46:945–952
Figure 13. Relative advantages of MR and PET imaging techniques to detect different
biochemical processes in brain tumors (gliomas). MRI detects alteration of blood-brain barrier
and extent of peritumoral edema. FDG-PET shows glucose metabolism, whereas increased
cell profileration can be imaged by [11C] Met and [18F] FLT.
Seminars in Nuclear Medicine, Volume 41, Issue 4, 2011, 246–264
1-(5-deoxy-5-[18F]-fluoro-α-D-arabinofuranosyl)-2nitroimidazole
(18F-FAZA)
The hypoxic region of many solid tumors has low
blood supply and decreased oxygen levels.
Hypoxic tumor tissue is associated with increased
resistance to therapy.
18F-FAZA
Nitroimidazoles such as the nucleoside analogue FAZA enzymatically undergo a single
electron reduction after entering the cell to form a reactive anion radical species.
RNO2
RNO2
out
1e
.-
RNO2
1e
further reduction
trapping
in
.
O2 -
O2
In hypoxic tissue the low oxygen concentration is not able to effectively compete to
reoxidize the molecule and further reduction appears to take place, culminating in the
association of the reduced nitroimidazole with various intracellular components.
.
PET Image Contrast
MRI
FDG (metabolism)
T4 FAZA* (hypoxia)
Cross Cancer Institute
6-[18F]Fluoro-L-DOPA [18F]FDOPA
Multi-target PER
1.
Neurology/Psychiatry:
• used for the study of presynaptic striatal dopaminergic function
in neurologic disorders.
• Biodistribution resembles the normal distribution of L-DOPA.
Like L-DOPA, it crosses the blood-brain barrier, where it is
converted to 18F-Fluorodopamine by DOPA decarboxylase.
•
18F-Fluorodopamine
is stored intraneuronally along with normal
L-dopamine in vesicles until the neuron activation triggers its
release and subsequent binding to the dopamine receptors.
6-[18F]Fluoro-L-DOPA [18F]FDOPA
2.
Oncology
a) Brain tumors:
•
18F-FDOPA has
been used for imaging of brain tumors as it
accumulates in both high grade and low grade gliomas.
• Intensity of tumor uptake may correlate with tumor grade and
cellularity.
• Changes in 18F-FDOPA uptake in brain tumors are potentially
useful for early response assessment.
(b) Neuroendocrine tumors (NET):
•
18F-FDOPA is
an excellent tracer for imaging NET as
overexpression of DOPA decarboxylase is a characteristic feature
of neuroendocrine tumors.
6-[18F]Fluoro-L-DOPA [18F]FDOPA
Availability of FDOPA was a problem however as methods of
synthesis had always been either electrophilic or isotopic exchange
reactions which resulted in a low radiochemical yields.
6-[18F]Fluoro-L-DOPA [18F]FDOPA
Recent success in nucleophilic synthesis of FDOPA allows
for much greater yield of this highly desired PER with the
potential for off site distribution.
SNMMI PET Center of Excellence and the Center for Molecular Imaging Innovation & Translation 2013
[18F]FDOPA
FDG
FDOPA
FDG
FDOPA
Figure 7: FDG PET (A,C) and FDOPA PET (B,E) results for a 68-yearold patient with clinical and biological suspicion of NET.
Cancer Imaging. 2012; 12(1): 173–184.
Positron emission tomography (PET) following administration of 18-fluoro-levodopa (18F-FDOPA) to label
dopaminergic terminals in the striatum.
José A. Obeso et al. Physiology 2002;17:51-55
82Rubidium
Chloride
Generator
The use of 82Rb Chloride for PET myocardial perfusion Imaging
(MPI) has been studied since the late 1950’s.
82Rb
is generator produced from 82Strontium which is cyclotron
produced and has a half life of 25 days.
82Rb
has a half life of 76 seconds with a maximum positron
energy of 3.36 MeV. Short half life good for MPI studies as
repeat and sequential perfusion studies are possible while
reducing patient exposure.
Brocco Diagnostics 82Rb Generator
82Rb
generators have been FDA approved for clinical use since
1989. Although the generator is approved in Canada, the
elution system is not and this necessitates the ongoing need for
CTA protocols.
Yoshinaga K. et. al. J Cardiol. 68, 2293-2297, (2010)
Jubilant DraxImage 82Rb
Elution System
82Sr/82Rb
Generator
•
•
82Sr
•
Adsorbed on SnO2
column
– Eluted with 0.9%Nacl
solution.
•
Life span
– 3-4 months.
•
Elution efficiency
– 85-95%
82
half life = 25days, EC
Rb half life = 75s, β+
Notes
• Injected directly from the generator
• Sterility precautions
• Needs to be eluted in physiological medium
• The RUBY-FILL® generator is approved by Health
Canada, but the Elution System is regulated as a medical
device.
82Rubidium
Chloride
Following I.V. injection, rubidium rapidly crosses the capillary
membrane and is extracted from the blood via the Na+/K+ ATPase
pump.
While MPI with SPECT agents remain the current standard of care,
PET has better spatial resolution, higher sensitivity and the ability to
measure tracer distribution in absolute terms as a function of time.
There are other short lived PET MPI agents such as H215O water and
13NH ammonia which offer even better spatial resolution and more
3
linear relationship with blood flow than 82Rb, but both require an onsite cyclotron for use.
The 82Rb generator is an attractive option for hospitals with no
cyclotron access.
Anagnostopoulos C et al., Int J Cardiol, 167,
1737-1749 (2013)
82Rubidium
Chloride
Figure 4. Representative images from normal subject and 47-year-old man with coronary
artery disease (CAD). (A) Normal subject: the 82Rb positron emission tomography (PET)
images show normal perfusion at stress and rest.
Keiichiro Yoshinaga, Ran Klein, Nagara Tamaki, Journal of Cardiology, Volume 55, Issue 2, 2010, 163–173
68Ga
Radiopharmaceuticals
Generators
•
Ga-68 is one of the earliest of the positron-emitting radionuclides used
in nuclear medicine, dating back to the early 1960s
•
Early 68Ga-generators provided 68Ga in complex with
ethylenediaminetetraacetic acid (EDTA) that made radiolabeling
tedious, time-consuming, and accomplished with overall poor yield.
By the late 1970s 68Ga-based PET imaging was replaced with 99mTc for
single photon emission computed tomography (SPECT) and 18F for
PET.
•
•
Not until 68Ge/68Ga generators became commercially available, which
enabled elution of cationic 68Ga with dilute acid (0.1 M HCl) did Ga68 chemistry gain widespread interest again.
•
Currently several 68Ge/68Ga generator systems are commercially
available from distributors in Russia, Europe, United States and other
countries.
Sangeeta R Banerjee, Martin G Pomper, Appl Radiat Isot 76, 2-13, (2013)
Sectional view of E & Z
Galliapharm Generator
68Ge/68Ga
Generator
Notes
• Eluate can contain 68Ge breakthrough
• Metal impurities decrease labelling
• i.e. 68Zn from Ga decay
• i.e. 71Ga from 71Ge decay (fresh generators)
• Ti and Fe can elute from the column
• Eluate Fractionation decreases metallic impurities
• Chromatographic purification can decrease impurities
•
•
68
•
Old Technology
– Adsorbed on tin
dioxide/alumina
– Eluent 1N HCl
•
New Technology
– TiO2,
– eluted with 0.1N HCl
– SnO2
– eluted with 0.6N HCl
•
Yield of gallium
– 75-80%
•
Shelf life
– 1 year
Ge half life = 271 days
68 Ga half life = 68 min,
68Ga
Radiopharmaceuticals
Cyclotron Production
The simplicity and lower capital cost of the 68Ge/68Ga generator have made it
more popular among the nuclear medicine facilities without cyclotrons.
However, the clinical promise of 68Ga-labeled radiopharmaceuticals indicated
the need for growth of the supply of 68Ga.
In addition, the breakthrough of long-lived 68Ge parent isotope (t½ = 271 d)
into the eluted 68Ga.
Small generator sizes and cost also remain a concern.
It is very feasible, although less convenient, to produce large quantities of 68Ga
for in-house use at facilities which already have a (low power) medical
cyclotron.
68Ga
from a 68Zn target is being used clinically in Portugal.
Am J Nucl Med Mol Imaging. 2014; 4(4): 303–310.
68Ga
Radiopharmaceuticals
Somatostatin Analogs
Somatostatin analogues
Sangeeta R Banerjee, Martin G Pomper, Appl Radiat Isot 2013
Almost synonymous with Ga-68
Exponential growth in last few years
~10,000 scans done annually in Europe (2013)
Figure 15. 68Ga-DOTATOC-PET in patient with multiple liver and lymph node metastases: Comparison
with 111In-DTPA-octreotide planar scintigraphy and [18F]fluoride-PET. Besides visceral metastases,
some additional osteoblastic and osteolytic bone metastases were clearly depicted with 68Ga-PET.
Osteoblastic bone lesions were confirmed by [18F]fluoride-PET. In contrast, only some of these bone
metastases were delineated by conventional 111In scintigraphy.
Gabriel M. et al. J. Nucl. Med 48, 508-518, (2007)
68Ga
Radiopharmaceuticals
As replacements for SPECT Agents i.e. 67Ga and 99mTc
Agent
Alternate
Indication
99mTc
ECD
68Ga
ECD
Cerebral Blood
Flow
99mTc
MAA
68Ga
MAA
Lung Imaging
99mTc
MDP
68Ga
EDTMP
Bone Imaging
99mTc
EDTA
68Ga
EDTA
Glomerular
Filtration Rate
68Ga
Citrate
Inflammation
67Ga
Citrate
Amir Reza Jalilian Iran J Nucl Med 2016;24(1):1-10
68Ga
Radiopharmaceuticals
Clinical Trial Products
68Ga-HBED-CC-PSMA
Amir Reza Jalilian Iran J Nucl Med 2016;24(1):1-10
68Ga
Radiopharmaceuticals
PSMA
One of the first PSMA inhibitors available for labeling
with 68Ga and PET imaging of PCa was the DOTA
conjugated urea-based PSMA inhibitor
However newer chelators such as the 68Ga-HBED-CCPSMA analog with better thermodynamic stability and
possibly better imaging characteristics are now in clinical
trials
patient with locally recurrent PCa (PSA 3.7 ng/ml) after radical
prostatectomy (SUVmax 12.4)
140 MBq 68Ga-HBED-CC-PSMA at 1 h p.i.;
a) CT image, b) PET image, c) PET/CT fusion image, d) MIP
Lütje S, Heskamp S, Cornelissen AS, Poeppel TD, Broek SAMWvd, Rosenbaum-Krumme S, Bockisch A, Gotthardt M, Rijpkema M, Boerman OC.
PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status. Theranostics 2015; 5(12):1388-1401.
Thank you for your attention.
Questions ?