“Graduate Studies in Radiochemistry at University of Missouri”

1. “Graduate Studies in Radiochemistry at University of Missouri” Susan Z. Lever Biomedical Program Director, MURR Associate Professor of Chemistry

2. Highest concentration of “radiochemistry” research scientists on any campus Breadth and diversity of research topics Vet School, Med School on the same campus Interdisciplinary research possibilities Law School, Business School on campus Student population has a range of interests Journalism School and School of Education Cross-discipline possibilities Things to know about MU #1:

3. Highest flux research reactor of any US campus High field nmrs, with an 800 MHz on order Cyclotron to be installed in 2007 Small animal imaging capabilities include SPECT, PET, MRI and CT Things to know about MU #2:

4. Radiopharmaceutical Science Program at MU Chemistry Biochemistry MURR Veterinary Medicine Radiology Internal Medicine

5. Long history of radiopharmaceutical development Established program in archeometry World-renowned location for contribution of trace metal analyses to biomedical problems Active grant funding and current projects in the above areas Things to know about MU #3:

6. Ceretec - a Neutral Tc-99m Complex • Ceretec is used for the diagnosis of abnormalities of regional cerebral blood flow • Epilepsy • Alzheimer's Disease

8. Blood Flow during Meditation Andrew Newberg, University of Pennsylvania http://www.andrewnewberg.com/ accessed 6/21/05

9. Design, synthesis and evaluation of novel biological targets for diagnosis and therapy Metal-Ligand Conjugate Tumor Cell Organic Linker Receptor Biomolecule Bifunctional Chelate Approach Thiolactone containing molecule was designed to permit one-step coupling with amine functionalities, and concomitant completion of the tetradentate core required for complexation.

10. Presence of the N-Methyl group yields charged complexes upon reaction with technetium. Bifunctional Chelate Approach for LabelingPeptides, Proteins and Antibodies with Tc Step 1. Step 2.

11. Approaches to radiolabeling diprenorphine with radioiodine Diprenorphine

12. Radioiodination via vinylstannylatedalkylating agents J. L. Musachio and J. R. Lever, Tetrahedron Lett., 30, 3613-3616 (1989)

13. C6-O-iodoallyl-diprenorphine forin vivo studies of opioid receptors O-IA-DPN Lever et al., Synapse 29: 172-182, 1998.

14. Radiosynthesis of[125/123I]-O-IA-DPN [125I]-O-IA-DPN 70 - 80% Radiochemical Yield 1200 - 1700 mCi /mol [123I]-O-IA-DPN 58 - 84% Radiochemical Yield > 2400 mCi /mol 2 Hours Total Time 1. NaI125/123 MeOH / HOAc (95:5) Chloramine-T, 2 min. 2. HPLC / Solid Phase Extraction 3. Formulation / QC (5% EtOH /saline)

15. [123I]-O-IA-DPN Allows Ex Vivo AutoradiographicLocalization of Opioid Receptors in Mouse Brain (1 hr) Saline Control Naltrexone Block

16. I I SA4503, FESA4503 and Initial Analogs E - iodoallyl SA4503; R = 11CH3 FESA4503; R = 18FCH2CH2- R = Z - iodoallyl Elsinga et al., Synapse 43:259-267, 2002. Ishiwata et al., Nucl. Med. Biol. 30:273-284, 2003.

17. Synthetic Scheme for Iodoallyl Analogs

18. In Vitro Binding Affinity (IC50 nM)of Z- and E-Iodoallyl Analogs of SA4503 Sigma-1 Sigma-2 SA4503 FE SA4503 E-IA SA4503 Z-IA SA4503 17.4a 6.48b 24.50 ± 1.61c 15.10 ± 1.03c 1784.1a 2.11b 22.0 ± 2.78c 20.3 ± 1.29c • a Matsuno et al, Eur J Pharm 306:271-279, 1996. • b Elsinga et al, Synapse 43:259-267, 2002. • c n=4, Mean ± SEM

19. Radiochemical Synthesis Radiochemical Yields with 125I: (57-58.5%) with high Specific Activity

20. Biodistribution of 125I-Iodoallyl Analogs of SA4503 in normal mice: Whole Brain Whole brain: Control and Blocked

21. Question: So, is there a chemical way to: 1) Decrease Lipophilicity and Retain Affinity?

22. New Iodoallyl analogs:

23. Biodistribution of “New and Improved” E125I-Iodoallyl Analog in normal mice:

24. In vivo performance of “New and Improved” Trans IA-Sigma Ligand Test drugs i.v. at 2.5 mol / kg. Values are means ± SD; n = 4.

26. Radiopharmaceutical Chemistry also deals with Radiotherapy

27. Highest neutron flux of any U.S. university reactor High reliability -- operates 105% of schedule [91% of clock time] Traditionally access samples once/week Currently access samples several times each week Features of MURR

28. The Blue Glow

29. Lanthanides [all M3+] Pm-149, Sm-153, Ho-166, Dy-166, Lu-177 Transition Metals Rh-105, Pd-109, Re-186, Ir-192, Au-198 Main Group Elements P-32, P-33, Se-75 Selected IsotopesCurrently Supplied by MURR

30. Isotope Half-Life Decay Ave Range Approx. Range (days) b - (MeV) (mm water) (cell diameters) Dy-166 3.40 0.40 0.18 15 Lu-177 6.71 0.50 0.24 20 Sm-153 1.93 0.69 0.35 30 Pm-149 2.21 1.1 0.71 60 Ho-166 1.12 1.9 1.38 117 Y-90 2.67 2.28 1.77 150 Nuclear Properties of Various M3+ Radionuclides

31. PO H 3 2 PO H 3 2 N N PO H 3 2 PO H 3 2 + 153Sm 153Sm-EDTMP [Quadramet] 99mTc-MDP 153Sm-EDTMP

32. Sm-153 identified as a useful nuclide for radiotherapy by MU researchers Development began in early 1980’s at MU in collaboration with the Dow Chemical Company [phosphonate ligands] Successful in palliative treatment of bone cancer in canine patients, with added bonus of ~ 15% cure rate [MU College of Veterinary Medicine program of Comparative Oncology] Clinical trials began in late 1980’s, with doses supplied by MURR for Phase I studies ~ 80% efficacy, with ~ 25% obtaining full pain remission Approved in U.S. for pain palliation of metastatic bone cancer in March, 1997 Story of QuadraMetTM

33. Nearly 100% blood supply of a liver tumor comes from hepatic artery Effective treatment with minimal toxicity Outpatient procedure Yttrium-90 Microspheres

34. Average diameter of microspheres - 20 -30 mm Yttrium is an integral part of the glass matrix Delbert Day (University of Missouri - Rolla) and Gary Ehrhardt (University of Missouri - Columbia) U.S. Patent 4,789,501 December 6, 1988 Yttrium-90 Microspheres

35. Y-89 microspheres are irradiated in the MU-Research Reactor (MURR), resulting in the conversion of the non-radioactive yttrium to Y-90, a powerful b- emitter (64.2 hr half-life, average distance in tissue: 2.5 mm) Preparation of Active Microspheres

36. In a recent study (Dancy et al., J. Nucl. Med. 41: 1673-1681, 2000), patients with hepatocellular carcinoma (HCC) were treated with 100 Gy Outcome: 79% patients decreased or had stable disease for a median of 10.3 months vs. 1 - 4 months for untreated patients Yttrium-90 Microspheres

37. March, 2000: MDS Nordion (Kanata, Ont. Canada) was granted a Humanitarian Device Exemption by the U.S. Food and Drug Administration as an alternative to chemotherapy in inoperable cases Yttrium-90 Microspheres become TheraSphere®

38. Five year grant award from the National Cancer Institute of the National Institutes of Health, 8/01/03 - 7/31/08 Complements on-going interdisciplinary research at MU focused on imaging and therapeutic applications of radioisotopes Includes a career development component, supporting undergraduate research activities. Centerfor Single Photon-EmittingCancer Imaging Agents

39. Departmental Research Interests Radiochemistry Analytical Environmental Interdisciplinary Research Inorganic Physical Materials Organic

40. Radiochemistry Program • Chemistry Department • Radiopharmaceutical Chemistry (Organic/Inorganic) • Radioanalytical Chemistry • Actinide Chemistry (Inorganic) • Radioenvironmental Chemistry • University of Missouri Research Reactor • Radioisotope Production (medical and biological isotopes) • Trace Analysis (archaeometry, epidemiology, environmental science) • Material Science

41. Jurisson Group Research • Radiopharmaceutical Chemistry • Inorganic Chemistry • Tc, Re, Rh, Au, Ln • Ligand design • Radiochemistry • Biochemistry/Biology • Radioenvironmental Chemistry

42. Research in the Duval Group Probes new coordination environments of actinides that bridge non-aqueous complexes with traditional systems found under environmental conditions.

43. J. David Robertson Using the unique properties of the nucleus to study chemical processes/problems which, frequently, cannot be examined by other means. Investigating the source and impact of fine airborne particulate Elemental imbalances in the formation of Alzheimer’s disease “Aging” the plaques and tangles in Alzheimer’s disease Using red ochre for provenance studies Evaluating children’s chronic exposure to As and Cr from Cu/Cr/As treated wood structures.

44. MURR Archaeometry Lab • NAA became the preeminent technique in archaeometric materials analysis following the pioneering work at the national labs in the late 1960s and early 1970s • unequalled replicability • sensitivity down to sub-ppm level • almost no matrix effect • fully instrumental, multi-element characterization

45. Collaborative projects with US archaeologists at academic institutions or museums in 46 states • Service to cultural resource management (CRM) archaeologists in 15 states • Collaborations with archaeologists in 15 countries in the Americas, Europe, the Middle East, and Far East

46. Population-Based Studies:Cancer incidence or mortality is inversely proportional to regional indicators of status. Case-Control Studies:In some case-control studies, selenium status, measured in a prospectively-collected biologic monitor, is lower in cancer cases compared to matched controls. Intervention Trials:Cancer incidence and mortality risks are lower among participants taking a supranutritional selenium supplement compared to control subjects in double-blind, placebo-controlled trials. Epidemiological studies have associatedlow selenium intake with increased cancer risk

47. http://www.smartdraw.com/

48. Active Graduate Student Organization Geographically south of the glaciated till plain, so rolling hills heading to the Ozarks Numerous caves for spelunking and rivers for floating In between Kansas City and St. Louis Things to know about MU #4: