Positron Emission Tomography Basics: Radiochemistry. N. Scott Mason, Ph.D. Radiochemist University of Pittsburgh PET Facility

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1 Positron Emission Tomography Basics: Radiochemistry. Scott Mason, Ph.D. Radiochemist PET Facility

2 What is PET? Positron Emission Tomography In-Vivo Imaging and Quantification of rgan/tissue Function Uses Positron-Emitting Radiolabeled Tracers

3 What is PET? Positron Emission Tomography In-Vivo Imaging and Quantification of rgan/tissue Function Uses Positron-Emitting Radiolabeled Tracers

4 PET Imaging 1. Cyclotron 2. Radionuclide 3. Radiosynthesis 4. PET Imaging 5. Image Reconstruction 6. Data Analysis

5 PET Imaging 1. Cyclotron 2. Radionuclide 3. Radiosynthesis 4. PET Imaging 5. Image Reconstruction 6. Data Analysis

6 Cyclotron

7 Positron Emitting Radionuclides Atoms that can be included in amino acids, carbohydrates, steroids, water, other small molecules, etc. (F is isostere for H) Short half-life: maximizes SR to subject radiation dose, but also means the isotope must be produced locally ( 18 F can be shipped) Half-life (min)" 18 F 109! 11 C 20! 13 10! 15!2!

8 Radionuclide Production Cyclotron! Stable uclide! 11 MeV protons! 18! Unstable Radionuclide! n! 18 F!

9 Radionuclide Production 15 2 p,n 15 2 H 2 16 p,α 13 H p,α 11 C2 H 2 18 p,n H 18 F

11 Potential C-11 Chemistry 11 CH 3 Tf 11 CH 3 Li 11 CH CH 3 I 11 CH 3 H H 11 CH 11 C 2 (CH 3 ) 2 11 C R 11 C 2 MgBr R 11 CH 2 H R 11 C 2 H R 11 CH 2 I R 11 CH R 11 CCl R 11 CH 2 R 11 CHR R 11 CR 2

12 C-11 Carboxylation Chemistry 11 CH 3 Tf 11 CH 3 Li 11 CH CH 3 I 11 CH 3 H H 11 CH 11 C 2 (CH 3 ) 2 11 C R 11 C 2 MgBr R 11 CH 2 H R 11 C 2 H R 11 CH 2 I R 11 CH R 11 CCl R 11 CH 2 R 11 CHR R 11 CR 2

13 [C-11]WAY * Me * Two potential labeling sites

14 [C-11]carbonyl WAY MgCl [C-11]C 2 * - * Cl + Me H Me * [C-11]carbonyl WAY100635

15 C-11 Methylation 11 CH 3 Tf 11 CH 3 Li 11 CH CH 3 I 11 CH 3 H H 11 CH 11 C 2 (CH 3 ) 2 11 C R 11 C 2 MgBr R 11 CH 2 H R 11 C 2 H R 11 CH 2 I R 11 CH R 11 CCl R 11 CH 2 R 11 CHR R 11 CR 2

16 [C-11]MeI System

17 [C-11]MeI System [ 11 C]Methyl Iodide System

18 [C-11]β-CFT chemistry H 3 11 C H CCH µl acetone [C-11]CH 3 Tf CCH 3 F 2 60 o C HPLC purification F

MPTP associated toxicity resulted in ~90% loss of DAT

19 [C-11]β-CFT micropet Imaging of Simian Unilateral MPTP Lesion Model of Parkinson s Disease Lesioned Striatum MPTP associated toxicity resulted in ~90% loss of DAT sites in left striatum as determined by PET Intact Striatum

20 Dopamine D2/D3 Imaging: [C-11]FLB457 H H [ 11 C]CH 3 Tf ah H 11 CH 3 Br Me Acetone Br Me

21 Dopamine D2/D3 Imaging: [C-11]FLB457 Specific Activity Concerns Ratio of radioactivity to cold mass Expressed as Ci/mmole Theoretical 9.4 x 10 6 Routinely achieved 2 x 10 3 Minimize cold mass associated with radioactivity administration (0.6 µg) Atmospheric C 2 acts to decrease specific activity

22 [C-11]Pittsburgh Compound B [C-11]PIB H S H 2 [ 11 C]CH 3 Tf Methyl Ethyl Ketone H S 11 CH 3 H 6-H-BTA-0 [ 11 C]6-H-BTA-1

23 [C-11]PIB Images Examples of Pittsburgh Compound-B (PIB) Logan DVR images for a control, a control-like mild cognitive impairment (MCI-2), an AD-like MCI (MCI-4), and the AD (AD-1) subject with highest PIB retention.

24 F-18 Fluoride Alkyl nucleophilic substitution (S2) Aromatic nucleophilic substitution (S2Ar) Issues Cation exchange and relatively anhydrous conditions

25 [F-18]FDG chemistry Ac H Ac Tf Ac 1. K[ 18 F], K HCl H H Ac H 18 F

26 [F-18]FDG chemistry

27 [F-18]FLT chemistry DMTr 1. K[ 18 F], K222, DMS 2. HCl H H 18 F

28 [F-18]FLT uptake in mice bearing xenografted SCCH tumors brain tumors

29 Metabolite Contribution H S [F-18]Altanserin 18 F H S H H [F-18]Altanserinol 18 F H 18 F [F-18]4-(4-Fluorobenzoyl)piperidine

31 Radiosynthesis of F-18]Altanserinol H S 2 H S K 18 F DMS hv 18 F EtH abh 4 H S H H 18 F

34 3 -[F-18]F-6-H-BTA-1 Radiochemistry H 36.54% S 18 F 20.92% HCH 3 [F-18]3'F-PiB Pr 2 2 S Pr % 4.00% CH 3 Precursors

35 3 -[F-18]F-6-H-BTA-1 Semi-Preparative HPLC 36.54% 20.92% 12.03% 4.00% Prodigy DS-Prep 10 x 250 mm, 3/1/6 MeC/ MeH/ TEA Buffer, 1 ml/min 0-5min, 5 ml/min 5-10 min, then 8mL/min

36 3 -[F-18]F-6-H-BTA-1 Final Product QC 36.54% 20.92% 12.03% 4.00% Prodigy DS-3 5µ 4.6 x 250 mm, 40% MeC / 60% TEA Buffer, 2.0 ml/min

37 The Regional Distribution of [18F]3 F-PiB in AD Brain is Very Similar to that of [11C]PiB

38 Radiopharmacy Quality Control Visual ph T 1/2 determination Radiochemical Identity Radiochemical Purity Chemical Purity (Specific Activity) Residual Volatile rganic Solvent Endotoxin Testing Sterility

39 Acknowledgments Chester A. Mathis, Ph.D. - Director Chemists Scott Mason Steve Kendro icole DeBlasio April Radelet Guo-feng Huang Physicists Julie Price Brian Lopresti Chip Laymon Eoin Carney Technologists James Ruszkiewicz Denise Ratica Collaborators Raj arendran Clayton Wiley Bill Klunk Jerry Schatten Jennifer Grandis Funding: IA, IMH, CI, CRR, UPMC

Radiochemistry and Radiopharmacy III

Radiochemistry and Radiopharmacy III Compact course held at UFSCAR, September 20123 Ulrich Abram Freie Universität Berlin Institute of Chemistry and Biochemistry Radiochemistry and Radiopharmacy 1. Fundamentals