Positron Emission Tomography (PET): Synthesis of short-lived 11 C and 18 F radionuclide tracers Sarah Decato 2/16/2012 Ostrovsky, G. (accessed 1/29/2011).

Background Outline Imaging Modalities PET physics PET radionuclides Tracer parameters Ostrovsky, G. (accessed 1/29/2011). 2

Growth of PET 3 Jaroff, L. (accessed 2/10/12).

Imaging Modalities Anatomical Imaging: Visualization of body structure; can only diagnose structural abnormalities. o X-ray o Computed tomography (CT) o Magnetic resonance imaging (MRI) Molecular Imaging: Target unique tissues or cell types with specific probes with the aim to monitor and diagnose diseases, study biological processes, evaluate drug efficacy. o Positron emission tomography (PET) o Single-photon emission computed tomography (SPECT) 4 Ametamey, S. M., Chem. Rev. 2008, 108,

Imaging Modalities: PET Advantages No imaging “handle” necessary Mass of probe is subtoxicological Beneficial multimodality capability (PET/CT, PET/MRI) Imaging modality Form of energy Spatial resolution (mm) Acquisition time (s) Probe mass (ng) Tissue depth (mm) Cost PET Annihilation photons >300High Ultrasound Sound waves Low 5 Levin, C. S., European Journal of Nuclear Medicine and Molecular Imaging 2005, 32, S325-S345., Diagnostic Imaging (accessed 2/3/2012). CTOverlayPET

PET Physics: Positron Decay RadionuclideDecay product 11 C 11 B 18 F 18 O 13 N 13 C 15 O 15 N β+β+ ν Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, positronneutrino Spontaneous 6

PET Physics: Coincidence Event γγ ν β-β- β+β+ annihilation photon detection decay path Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47,

PET Radionuclides: Selection Nuclide Half-life (min.) Max. energy (MeV) Decay Mode (%) a Max. Specific Activity (GBq/µmol) 18 F x C x N x O x Br x I60, x Ga x Cu b 9.13 x 10 3 a Remaining decay percentage is from electron capture b Remaining decay percentage is from 41% electron capture and 40% β - decay 8 Ametamey, S. M., Chem. Rev. 2008, 108,

PET Physics: Cyclotron A charged particle moves through a magnetic field The beam travels in a circle and the particle accelerates through the electric field region (gap) Nuclear reaction occurs as the beam hits the target Ametamey, S. M., Chem. Rev. 2008, 108, , Encyclopedia Britannica classical-cyclotron-Subatomic-particles-introduced-into (accessed 2/2/2012). 9

PET Radionuclides: Synthesis TargetNuclear ReactionProduct 11 C N 2 (+O 2 ) 14 N (p,α) 11 C 11 CO 2 N 2 (+H 2 ) 11 CH 4 18 F Ne (+ 19 F 2 ) 20 Ne (d,α) 18 F 18 F- 19 F H 2 18 O 18 O (p,n) 18 F 18 F - target nucleus product nucleus accelerated particle emitted particle Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47,

UW - Madison UW – Madison Cyclotron/PET Research Center (accessed 2/2/2012). 11

Tracer Parameters Time o Half-life o Preparation time < 3 half-lives o Transport Scale (µL – nL) Modifications to biological properties ( 18 F) Label position o 2-fluoro-2-deoxy-glucose (FDG) Radiochemical yield (%RCY) Specific activity (GBq/µmol) o 74GBq/µmol 18 FDG 12 Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, , Zheng, Q.-H., et al., Biomed. Chromatogr. 2005, 19,

Synthesis Outline 11 C o Radiolabeling precursors o 11 CO 2 o 11 CO o Methylation 18 F o Radiolabeling precursors o Electrophilic fluorination o Nucleophilic fluorination o Iodonium salts o Late stage fluorination Yale School of Medicine (accessed 2/2/2012). 13

Radiolabeling Precursors: 11 C 14 N (p,α) 11 C 11 CO2 11 CH3I 11 CH3OTf 11 COR 11 CO2MgX 11 CH4 N 2 (+H 2 ) 1) LiAlH 4 2) HI “wet method” “dry method” N 2 (+O 2 ) I 2, 720°C Mo, 820°C RMgX AgOTf EOB 14 Pretze, M., et al., Molecules 2011, 16, , Scott, P. J. H., Angew. Chem. Int. Ed. 2009, 48, , Ametamey, S. M., Chem. Rev. 2008, 108, , Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47,

CO 2 : Grignard WAY Analog of 5-HT 1A receptor antagonist: p-MMPI 15 Hwang, D.-R., et al., Nuc. Med. Biol. 1999, 26, , Lu, S.-Y., et al., J. Label.Compd. Radiopharm. 2003, 46,

CO: Low Solubility CO does not suffer from significant isotopic dilution CO is limited by : o Low solubility in organic solvents o Low reactivity at or near atmospheric pressure 16 Audrain, H., et al., Chem. Commun. 2004, , Långström, B., et al., J. Label. Compd. Radiopharm. 2007, 50,

CO: Palladium-mediated Palladium-mediated 11 C-carbonylation reactions Stille Suzuki 17 Långström, B., et al., J. Label. Compd. Radiopharm. 2007, 50, , Rahman, O., et al., Eur. J. Org. Chem. 2004, 2004, , Karimi, F., et al., Eur. J. Org. Chem. 2005, 2005, , Hostetler, E. D., et al., Nuc. Med. Biol. 2002, 29, , Rahman, O., et al., Eur. J. Org. Chem. 2004, 2004,

Simple Methylation O, S, N alkylation Captive solvent method or loops allow for increased reactivity with milder conditions General method under mild conditions [ 11 C]raclopride [ 11 C]flumazanil Wilson, A. A., et al., Nuc. Med. Biol. 2000, 27, , Cleij, M. C., et al., J. Label. Compd. Radiopharm. 2007, 50, CH 3 I from cyclotron HPLC Trap Loop Detector

Methylation: Stille Cross-coupling Hosoya, T., et al., Org. Biomol. Chem. 2006, 4, , Samuelsson, L., et al., J. Label. Compd. Radiopharm. 2003, 46, , Hamill, T. G., et al., Synapse 2005, 56, FMAU M-TEB ligand (mGluR5) 19

Methylation: Suzuki Sanchez-Pernaute, R., et al., NeuroImage 2008, 42, , Hostetler, E. D., et al., J. Label. Compd. Radiopharm. 2005, 48, , Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, YRCY o-Br49-67% o-NO % p-OH92-95% m-CHO62-92% p-COOH69-72% p-COOMe80-93% p-NHCOMe85-96% 20

Methylation: Transfer Reagent 21 Forngren, T., et al., J. Label. Compd. Radiopharm. 2004, 47, , Huiban, M., et al., Chem. Commun ,

11 C Summary 11 CO 2 is a traditional yet mainly inefficient method to perform 11 C- labeling. 11 CO is versatile but needs to be modified or trapped to become effectively reactive. Direct methylation can be achieved with captive solvent methods or Pd-mediated cross-couplings with 11 CH 3 I. 22

18 O(p,n) 18 FK 18 F - “ 18 F - ” Radiolabeling Precursors: 18 F 20 Ne(d,α) 18 F 18 F– 19 F CH3CO218F 19 F 2 AcOH AcOK K 2 CO 3 H 2 O/ACN “K ” 23 Schirrmacher, R., et al., Mini-Reviews in Organic Chemistry, 2007, 4, , Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, , Pretze, M., et al., Molecules 2011, 16, ElectrophilicNucleophilic

Electrophilic Fluorination 18 F- L -Tyrosine 18 F- L -DOPA 24 Miller, P. W., et al., Angew. Chem. Int. Ed. 2008, 47, , Hess, E., et al., Appl. Radiat. Isot. 2002, 57,

Nucleophilic Fluorination FDG S N Ar most prevalent 18 F labeling technique Substitutions on heterocylic systems (pyridine) do not require activating groups (Y) MPPF 25 Furuya, T., et al., Synthesis 2010, 2010, , Ehrenkaufer, R. E., et al., Journal of Nuclear Medicine 1984, 25, , Telu, S., et al., Org. Biomol. Chem. 2011, 9, , Hamacher, K., et al., Journal of Nuclear Medicine 1986, 27,

Iodonium Salts 26 Wang, B., et al., J. Fluorine Chem. 2010, 131, , Littich, R., et al., Angew. Chem. Int. Ed. 2012, 51, , Ross, T. L., et al., J. Am. Chem. Soc. 2007, 129, , Pretze, M., et al., Molecules 2011, 16,

Iodonium Salts: Pd Coupling Precursor Stille Suzuki 27 Ross, T. L., et al., J. Am. Chem. Soc. 2007, 129, , Schirrmacher, R., et al., Mini-Reviews in Organic Chemistry, 2007, 4, , Pretze, M., et al., Molecules 2011, 16,

Late Stage Fluorination: Selectfluor Selectfluor bis(triflate) 28 Littich, R., et al., Angew. Chem. Int. Ed. 2012, 51,

Late Stage Fluorination: Ritter Catalyst fluorodeoxyestrone 29 Lee, E., et al., Science 2011, 334, , Furuya, T., et al., J. Am. Chem. Soc. 2010, 132, , Littich, R., et al., Angew. Chem. Int. Ed. 2012, 51,

Electrophilic fluorination results in low specific activity and low selectivity Nucleophilic methods are most common but limited to electron-deficient aromatic systems Iodonium salts allow for versatility and an efficient route to fluoro-iodobenzene, a precursor for Pd-mediated syntheses Current trends aim to develop more selective fluorinating reagents using Selectfluor-based methods and catalyst designs 18 F Summary 30

Future Directions Microfluidics Complete automation 31 Lee, C. C., Science 2005, 310, , (accessed 2/5/2012).

Acknowledgements Advisor: Dr. Sandro Mecozzi Group Members: Elham Nejati Aaron McCoy Dr. Jun-Pil Jee Will Tucker Ken Simmons Andrew Oskoui Matt Biller Special Thanks: Kat Myhre Joseph Moore 32 Practice Talk Attendees: Patrick Robichaux Aaron McCoy Ben Haenni Allice Dang Jon Jaworski Andrie Iosub Chris Adams Anna Dunn