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Sarah Decato 2/16/2012

Positron Emission Tomography (PET): S ynthesis of short-lived 11 C and 18 F radionuclide tracers. Sarah Decato 2/16/2012. Ostrovsky, G. http :// medgadget.com/2011/06/siemens-biograph-mmr-mrpet-scanner-gets-eu-green-light.html (accessed 1/29/2011). Background O utline.

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Sarah Decato 2/16/2012

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  1. Positron Emission Tomography (PET):Synthesis of short-lived 11C and 18F radionuclide tracers Sarah Decato 2/16/2012 Ostrovsky, G. http://medgadget.com/2011/06/siemens-biograph-mmr-mrpet-scanner-gets-eu-green-light.html (accessed 1/29/2011).

  2. Background Outline Imaging Modalities PET physics PET radionuclides Tracer parameters Ostrovsky, G. http://medgadget.com/2011/06/siemens-biograph-mmr-mrpet-scanner-gets-eu-green-light.html (accessed 1/29/2011).

  3. Growth of PET Jaroff, L. http://www.time.com/time/magazine/article/0,9171,998685,00.html (accessed 2/10/12).

  4. Imaging Modalities • Anatomical Imaging: Visualization of body structure; can only diagnose structural abnormalities. • X-ray • Computed tomography (CT) • 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. • Positron emission tomography (PET) • Single-photon emission computed tomography (SPECT) Ametamey, S. M., Chem. Rev. 2008,108, 1501-1516.

  5. Imaging Modalities: PET Advantages CT Overlay PET No imaging “handle” necessary Mass of probe is subtoxicological Beneficial multimodality capability (PET/CT, PET/MRI) Levin, C. S., European Journal of Nuclear Medicine and Molecular Imaging 2005,32, S325-S345., Diagnostic Imaging http://www.diagnosticimaging.com/display/article/113619/1412709?pageNumber=3 (accessed 2/3/2012).

  6. PET Physics: Positron Decay Spontaneous β+ ν positron neutrino Miller, P. W., et al., Angew. Chem. Int. Ed. 2008,47, 8998-9033.

  7. PET Physics: Coincidence Event decaypath ν γ γ β+ photondetection photondetection β- annihilation Miller, P. W., et al., Angew. Chem. Int. Ed. 2008,47, 8998-9033.

  8. PET Radionuclides: Selection aRemaining decay percentage is from electron capture bRemaining decay percentage is from 41% electron capture and 40% β-decay Ametamey, S. M., Chem. Rev. 2008,108, 1501-1516.

  9. PET Physics: Cyclotron Acharged 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, 4036-4036., Encyclopedia Britannica http://www.britannica.com/EBchecked/media/59676/Plan-view-of-a-classical-cyclotron-Subatomic-particles-introduced-into (accessed 2/2/2012).

  10. PET Radionuclides: Synthesis aX(d,n)bY target nucleus product nucleus emitted particle accelerated particle Miller, P. W., et al., Angew. Chem. Int. Ed. 2008,47, 8998-9033.

  11. UW - Madison UW – Madison Cyclotron/PET Research Center http://www.medsch.wisc.edu/cycl/default.html (accessed 2/2/2012).

  12. Tracer Parameters 18FDG • Time • Half-life • Preparation time < 3 half-lives • Transport • Scale (µL – nL) • Modifications to biological properties (18F) • Label position • 2-fluoro-2-deoxy-glucose (FDG) • Radiochemical yield (%RCY) • Specific activity (GBq/µmol) • 74GBq/µmol Miller, P. W., et al., Angew. Chem. Int. Ed. 2008,47, 8998-9033., Zheng, Q.-H., et al., Biomed. Chromatogr. 2005,19, 671-676.

  13. Synthesis Outline • 11C • Radiolabeling precursors • 11CO2 • 11CO • Methylation • 18F • Radiolabeling precursors • Electrophilic fluorination • Nucleophilic fluorination • Iodonium salts • Late stage fluorination Yale School of Medicine http://petcenter.yale.edu/index.aspx (accessed 2/2/2012).

  14. Radiolabeling Precursors: 11C N2 (+O2) N2 (+H2) EOB “wet method” “dry method” 1) LiAlH4 2) HI I2, 720°C Mo, 820°C RMgX AgOTf Pretze, M., et al., Molecules2011,16, 1129-1165., Scott, P. J. H., Angew. Chem. Int. Ed. 2009,48, 6001-6004., Ametamey, S. M., Chem. Rev. 2008,108, 1501-1516., Miller, P. W., et al., Angew. Chem. Int. Ed. 2008,47, 8998-9033.

  15. CO2: Grignard WAY100635 Analog of 5-HT1A receptor antagonist: p-MMPI Hwang, D.-R., et al., Nuc. Med. Biol. 1999,26, 815-819., Lu, S.-Y., et al., J. Label.Compd. Radiopharm. 2003,46, 1249-1259.

  16. CO: Low Solubility • CO does not suffer from significant isotopic dilution • CO is limited by : • Low solubility in organic solvents • Low reactivity at or near atmospheric pressure Audrain, H., et al., Chem. Commun. 2004, 558-559., Långström, B., et al., J. Label. Compd. Radiopharm. 2007,50, 794-810.

  17. CO: Palladium-mediated Stille Palladium-mediated 11C-carbonylation reactions Suzuki Långström, B., et al., J. Label. Compd. Radiopharm. 2007,50, 794-810., Rahman, O., et al., Eur. J. Org. Chem. 2004,2004, 2674-2678., Karimi, F., et al., Eur. J. Org. Chem. 2005,2005, 2374-2378., Hostetler, E. D., et al., Nuc. Med. Biol. 2002,29, 845-848., Rahman, O., et al., Eur. J. Org. Chem. 2004,2004, 474-478.

  18. Simple Methylation 11CH3I from cyclotron Trap [11C]raclopride HPLC Loop [11C]flumazanil Detector O, S, N alkylation Captive solvent method or loops allow for increased reactivity with milder conditions General method under mild conditions Wilson, A. A., et al., Nuc. Med. Biol. 2000,27, 529-532., Cleij, M. C., et al., J. Label. Compd. Radiopharm. 2007,50, 19-24.

  19. Methylation: Stille Cross-coupling FMAU M-TEB ligand (mGluR5) Hosoya, T., et al., Org. Biomol. Chem. 2006,4, 410-415., Samuelsson, L., et al., J. Label. Compd. Radiopharm. 2003,46, 263-272., Hamill, T. G., et al., Synapse 2005,56, 205-216.

  20. Methylation: Suzuki Sanchez-Pernaute, R., et al., NeuroImage2008,42, 248-251., Hostetler, E. D., et al., J. Label. Compd. Radiopharm. 2005,48, 629-634., Miller, P. W., et al., Angew. Chem. Int. Ed. 2008,47, 8998-9033.

  21. Methylation: Transfer Reagent Forngren, T., et al., J. Label. Compd. Radiopharm. 2004,47, 71-78., Huiban, M., et al., Chem. Commun. 2006., 97-99.

  22. 11C Summary 11CO2 is a traditional yet mainly inefficient method to perform 11C-labeling. 11CO 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 11CH3I.

  23. Radiolabeling Precursors: 18F Electrophilic Nucleophilic 19F2 K2CO3 H2O/ACN AcOHAcOK “K2.2.2” Schirrmacher, R., et al., Mini-Reviews in Organic Chemistry, 2007,4, 317-329., Miller, P. W., et al., Angew. Chem. Int. Ed. 2008,47, 8998-9033., Pretze, M., et al., Molecules2011,16, 1129-1165.

  24. Electrophilic Fluorination 18F-L-Tyrosine 18F-L-DOPA Miller, P. W., et al., Angew. Chem. Int. Ed. 2008,47, 8998-9033., Hess, E., et al., Appl. Radiat. Isot. 2002,57, 185-191.

  25. Nucleophilic Fluorination FDG SNAr most prevalent 18F labeling technique MPPF Substitutions on heterocylic systems (pyridine) do not require activating groups (Y) Furuya, T., et al., Synthesis 2010,2010, 1804-1821., Ehrenkaufer, R. E., et al., Journal of Nuclear Medicine 1984,25, 333-337., Telu, S., et al., Org. Biomol. Chem. 2011,9, 6629-6638., Hamacher, K., et al., Journal of Nuclear Medicine 1986,27, 235-238.

  26. Iodonium Salts Wang, B., et al., J. Fluorine Chem. 2010,131, 1113-1121., Littich, R., et al., Angew. Chem. Int. Ed. 2012,51, 1106-1109., Ross, T. L., et al., J. Am. Chem. Soc. 2007,129, 8018-8025., Pretze, M., et al., Molecules2011,16, 1129-1165.

  27. Iodonium Salts: Pd Coupling Precursor Stille Suzuki Ross, T. L., et al., J. Am. Chem. Soc. 2007,129, 8018-8025., Schirrmacher, R., et al., Mini-Reviews in Organic Chemistry, 2007,4, 317-329., Pretze, M., et al., Molecules2011,16, 1129-1165.

  28. Late Stage Fluorination: Selectfluor 1 Selectfluorbis(triflate) Littich, R., et al., Angew. Chem. Int. Ed. 2012,51, 1106-1109.

  29. Late Stage Fluorination: Ritter Catalyst 1 fluorodeoxyestrone 1 Lee, E., et al., Science 2011,334, 639-642., Furuya, T., et al., J. Am. Chem. Soc. 2010,132, 3793-3807., Littich, R., et al., Angew. Chem. Int. Ed. 2012,51, 1106-1109.

  30. 18F Summary 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

  31. Future Directions Microfluidics Complete automation Lee, C. C., Science 2005,310, 1793-1796., http://www.gehealthcare.com/euen/fun_img/products/radiopharmacy/products/fastlab-index.html (accessed 2/5/2012).

  32. Acknowledgements • Practice Talk Attendees: Patrick Robichaux Aaron McCoy Ben HaenniAlliceDang Jon JaworskiAndrieIosub Chris Adams Anna Dunn Advisor: Dr. SandroMecozzi Group Members: ElhamNejati Aaron McCoy Dr. Jun-PilJee Will Tucker Ken Simmons Andrew Oskoui Matt Biller Special Thanks: Kat Myhre Joseph Moore

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