radiopharmaceuticals in molecular imaging · eanm impd guidelines and toxicity position paper these...
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Radiopharmaceuticals in Molecular Imaging
Philip Elsinga IPET2015, IAEA headquarters Vienna
Nuclear Medicine and Molecular Imaging
Disclosure (potential) Conflict of interest None
For the meeting possible relevant relations with companies
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OH
18F
HO
Tracers: the Fuel for Nuclear Medicine
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Measuring different properties
[18F]FLT [18F]FDG [11C]MET
Glucose metabolism
Amino acid transporter
DNA synthesis
Medical Imaging Center 6-10-2015
PET tracers: nuclide selection
Endogenous compounds (“Elements of life”)
Synthetic potential
Physical vs. biological half-life
Biomolecules (peptides, proteins, oligonucleotides)
11C (13N, 15O)
11C, 18F
11C, 18F, 124I 68Ga, 64Cu, 89Zr
68Ga, 64Cu, 89Zr
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- Appearance - pH
- Radiochemical purity (UPLC, HPLC, TLC) - Chemical purity (UPLC, HPLC) - Specific activity (UPLC, HPLC) - Residual solvents - Endotoxins - Sterility - Osmomolarity
- Radionuclidic purity (gamma spectroscopy) - Half-life
Before batch release
After batch release
Constraint Time: Quality control
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Use of PET Isotopes Including Radiometals
0
100
200
300
400
500
600
Num
ber o
f Pub
licat
ions
: Rad
iotr
acer
s (P
ubm
ed)
1980-1985
1986-1990
1991-1995
1996-2000
2001-2005
2006-2010
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Some possibilities of carbon-11 11CO2
11CO
11CH4
H11CN 11CH2O
11CH3OH
11CH3I 11CH3I
Zn 400 °C
Ni, H2 360 °C
I2 (g) 720 °C
LiAlH4 -40 °C
LiAlH4 , 20 °C
HI 130 °C
Pt, NH3 360 °C
11CHCl3
11CH2N2
H2NNH2 KOH, 60 °C
Cl2, CuCl2 310 °C
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11CH3 examples
Flumazenil PK11195 Verapamil
Raclopride SCH23390 DASB
Deprenyl PIB
N
N
N O
O
O
F
11CH3
NN
O
Cl
11CH3
NO
O N
O
O
11CH3
O
NH
N
ClO
OHCl
11CH3
N 11CH3
Cl
HO
S
NH2
N11CH3
N
N
H11CH3
HO S
NNH
11CH3
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Tracers for oncology applied in humans Name target category 11C-HTP 5-HT storage in NET transporter/enzyme substrate 11C-methionine amino acid transport transporter substrate 11C-choline membrane synthesis enzyme substrate 11C-acetate oxidative metabolism enzyme substrate
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Workhorse of PET: [18F]FDG [18F]FDG
OH
18FOH
HO
OHO
OAc
18FOAcAcO
OAcO
OAc
OSO2CF3OAc
AcO
OAcO
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Peptide labeling with Fluoride-18
18F
O
ON
O
O
18FHN
OH2N
18F
O
NH
OO
H2NNH
OO
N
18F
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New trends in 18F-chemistry -Al18F peptide labelling -electron-poor arenes: sulphoxides, boronic acids or aryl iodonium salts -High SA electrophilic 18F
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New developments Fluor-18 as fluoride, react with Pd complex after which Fluor-18 reacts as electrophile
[18F]AlF, 18F labeled aluminum fluoride and NOTA for peptide labeling
+ Al18F
[18F]fluoride + AlCl3
N
NN
O
HN
HOO
O
OH
N
NN
O
HN
HOO
O
OH
Al
18F
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Tracers for oncology applied in humans Name target category 18F-FDG glucose consumption enzyme substrate 18F-FLT DNA-synthesis enzyme substrate 18F-choline membrane synthesis enzyme substrate 18F-DOPA DA-storage in NET transp/enzyme substrate 18F-ethyltyrosine amino acid transport transporter substrate 18F-sodiumfluoride bone scan ion exchange 18F-FDHT Androgen receptor receptor antagonist 18F-fluoroestradiol ES-receptor receptor antagonist 18F-5-fluorouracil chemotherapy enzyme substrate 18F-fluoro-octreotide SSR receptor agonist 18F-FMISO hypoxia enzyme substrate 18F-FAZA hypoxia enzyme substrate 18F-RGD alphaV-beta3 integrin receptor antagonist
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68Ga-radiochemistry • Properties of 68Ga • GMP-compliance of generator • Elution prepurification • Chelator (DOTA, NOTA, new chelators) • Application to peptides only ?
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68Ga-peptides
• DOTATATE/TOC SST2 • 68Ga-PSMA-HBED-CC PSMA • BAPEN derivatives myocardial blood flow • bombesin GRPR
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89Zr-cetixumab, EGFR imaging in tumor bearing mice
H.J. Aerts, J. Nucl. Med 2009
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Overview of 89Zr radiolabelled antibodies
89Zr-trastuzumab HER2/neu 89Zr-bevacizumab EGFR 89Zr-cetuximab VEGF 89Zr-Ro5233441 Placental Growth Factor 89Zr-Panitumumab EGFR 89Zr-PGN635 Phosphatidylserine 89Zr-TRC105 CD105 89Zr-cG250-F(ab')2 Carbonic anhydrase
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Conclusions PET-radiochemistry •11C: CO-chemistry
•18F: simplification
•Increased use of PET-radiometals 68Ga, 89Zr, 64Cu and 44Sc
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Trends in PET-tracer development -Antibody fragments, affibodies -Nanoparticles -Enzyme substrates -Apoptosis tracers -Tracers voor neurodegeneration including Alzheimer tracers -Neuroinflammation -Agonists, endogenous neurotransmitter levels -Drug development purposes Validation of PET-tracers is needed -Multicenter trials -Harmonization of legislation
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Hybrid radiopharmaceuticals
• PET (for diagnosis) combined with:
• Optical imaging including Cerenkov, intraoperative imaging
• MRI to compensate for limitations of PET
• CT (anatomical information)
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What will dual imaging bring us ?
• Use of complementary benefits to eliminate the weaknesses of nuclear imaging:
• Poor anatomical localization
• Use of radioactivity
• Validation of one technique by aid of the other
• Complementarity with respect to sensitivity, spatial resolution, quantification
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Probes for Optical Imaging Main application in intraoperative imaging, analysis on cellular level Fluorescent proteins – bioluminescence (BLI) do not allow NIF Fluorescent small dye molecules, mostly non-targeted, Folate-FITC Cerenkov – beta emission Quantum dots (Cd/Te or Cd/Se) FDA-approval, toxicity…….
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Main application of PET-optical imaging radiopharmaceuticals: PET for diagnosis and localization, OI for accurate surgery and delineation
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Paulus et al, EJNMMI Res (2015) 5:43
Evaluation of [18F]BODIPY-Bombesine in the mouse
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Cerenkov imager by Lightpoint Medical
[18F]FDG: PET and Cerenkov imaging, Spinelli et al Physica medica (2015)
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Facilitating Development of New Imaging
Biomarkers and New Radiopharmaceuticals
The European perspective
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European laws and rules
Directives Must be transposed to be effective
Regulations Are immediately enforceable
Other rules
Decisions of the Council Opinions Recommendations
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Regulatory basis for the use of radiopharmaceuticals
Marketing Authorisation
Clinical Trial
„Extemporaneous Preparation“
Compounding In-house
Directive 2001/83 (Medicinal Products for human use) as
amended by 2004/27:
Directive 2001/20/EC
Directive 2003/94/EG
Directive 2005/28/EC
National Competence
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Problematic issues
• Reaching First in man studies • Marketing Authorizations • Clinical trials • Good Manufacturing Practice
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Legislation on Radiopharmaceuticals
Regulations on industrial manufacturing (GMP) Regulations on registration and marketing authorization Regulations on clinical trials European Pharmacopoeia
What do we share in Europe?
Individualize RP from other medicinal products Common regulations for:
Extemporaneous preparation of RP PET RP compounding for in-house use Inspection
What would we need?
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Toxicity tests yes/no ? – What is known on the compound ?
– Have studies been performed elsewhere ?
– What is the dose ? Microdosing concept
– Which patient population ?
– Practical aspects: Biomolecules <-> small molecules
– Biodistribution / dosimetry
– Extended single dose toxicity
– A position paper on toxicity of Radiopharmaceuticals is drafted
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EANM IMPD GUIDELINES and TOXICITY POSITION PAPER
These documents summarize the views of the Radiopharmacy Committee and the Drug Development Committee of the EANM and reflects recommendations.
For IMPD: Examples: 11C-choline, 68Ga-DOTANOC, 177Lu-peptide
Toxicity: Clarifications and recommendations regarding application of amounts
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Alternatives to “Eudralex” GMP cGRPP- Radiopharmacy Committee EANM
http://www.eanm.org/scientific_info/guidelines/gl_radioph_cgrpp.pdf
Guidelines for preparation of RP
Guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals in automated modules (in progress)
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Modulation of impact assessment based on real risk
to subject safety
GMP not requested for preparation of diagnostic
RP for CT
Special requirements for labelling
of primary packaging
Clinical Trials Regarding radiopharmaceuticals,
several important specific exceptions were introduced
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Radiopharmaceuticals in Molecular Imaging take home message • The applications of PET radiopharmaceuticals are virtually unlimited
• Combination of PET-tracers with other imaging modalities starts to
be explored
• The chemistry tools available for the preparation of PET tracers are still limited but toolbox for preparation gets bigger
• Legislation for clinical preparation (GMP) shows tendency to become more risk-based
• Multi-center trials are required to achieve breakthrough in clinical application of more new PET-tracers