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

Things to know about MU #1: 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 #2: 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

Radiopharmaceutical Science Program at MU Chemistry Biochemistry VeterinaryMedicine Radiology InternalMedicine MURR

Things to know about MU #3: 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

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

Andrew Newberg, University of Pennsylvania accessed 6/21/05 Blood Flow during Meditation

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

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

Approaches to radiolabeling diprenorphine with radioiodine Diprenorphine

Radioiodination via vinylstannylated alkylating agents J. L. Musachio and J. R. Lever, Tetrahedron Lett., 30, (1989)

Lever et al., Synapse 29: , C6-O-iodoallyl-diprenorphine for in vivo studies of opioid receptors O-IA-DPN

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

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

SA4503, FESA4503 and Initial Analogs Elsinga et al., Synapse 43: , Ishiwata et al., Nucl. Med. Biol. 30: , SA4503; R = 11 CH 3 FESA4503; R = 18 FCH 2 CH 2 - R = I I E - iodoallyl Z - iodoallyl

Synthetic Scheme for Iodoallyl Analogs

In Vitro Binding Affinity (IC 50 nM) of Z- and E-Iodoallyl Analogs of SA4503 Sigma-1Sigma-2 SA4503 FE SA4503 E-IA SA4503 Z-IA SA a 6.48 b ± 1.61 c ± 1.03 c a 2.11 b 22.0 ± 2.78 c 20.3 ± 1.29 c aMatsuno et al, Eur J Pharm 306: , bElsinga et al, Synapse 43: , cn=4, Mean ± SEM

Radiochemical Synthesis Radiochemical Yields with 125 I: ( %) with high Specific Activity

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

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

New Iodoallyl analogs:

Biodistribution of “New and Improved” E I- Iodoallyl Analog in normal mice: Biodistribution of “New and Improved” E 125 I- Iodoallyl Analog in normal mice:

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

Radiopharmaceutical Chemistry also deals with Radiotherapy

Features of MURR 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

The Blue Glow

Selected Isotopes Currently Supplied by MURR Lanthanides [all M 3+ ] –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

Nuclear Properties of Various M 3+ Radionuclides IsotopeHalf-LifeDecayAve RangeApprox. Range (days)  - (MeV) (mm water)(cell diameters) Dy Lu Sm Pm Ho Y

153 Sm-EDTMP [Quadramet] 99m Tc-MDP 153 Sm-EDTMP N N PO 3 H 2 3 H 2 3 H 2 3 H Sm +

Story of QuadraMet TM 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

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

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

Preparation of Active Microspheres 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  - emitter (64.2 hr half-life, average distance in tissue: 2.5 mm)

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

Yttrium-90 Microspheres become TheraSphere ® 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

Center for Single Photon-Emitting Cancer Imaging Agents  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.

Departmental Research Interests Analytical Inorganic Organic Physical Environmental Materials Radiochemistry InterdisciplinaryResearch

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

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

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

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.

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

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

Epidemiological studies have associated low selenium intake with increased cancer risk 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.

Things to know about MU #4: 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