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

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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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[11C]carbonylations

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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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Chelators for 68Ga

J. Notni et al, Chem Eur J, 2011, 17, 14718

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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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Development 89Zr-antibodies

Verel et al, J Nucl Med. 2003

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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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Combined PET and fluorescence

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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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The Rules

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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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The Problems

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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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The Solutions

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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

Thank you for your attention