“ 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
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 Veterinary Medicine Radiology Internal Medicine 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
Andrew Newberg, University of Pennsylvania http://www.andrewnewberg.com/ 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 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, 3613-3616 (1989)
Lever et al ., Synapse 29: 172-182, 1998. C6-O-iodoallyl-diprenorphine for in vivo studies of opioid receptors O-IA-DPN
[ 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 43:259-267, 2002. Ishiwata et al., Nucl. Med. Biol. 30:273-284, 2003. SA4503; R = 11 CH 3 FESA4503; R = 18 FCH 2 CH 2 - R = E - iodoallyl Z - iodoallyl I I
Synthetic Scheme for Iodoallyl Analogs
In Vitro Binding Affinity (IC 50 nM) of Z - and E -Iodoallyl Analogs of SA4503 Sigma-1 Sigma-2 SA4503 FE SA4503 E -IA SA4503 Z -IA SA4503 17.4 a 6.48 b 24.50 ± 1.61 c 15.10 ± 1.03 c 1784.1 a 2.11 b 22.0 ± 2.78 c 20.3 ± 1.29 c
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
Radiochemical Synthesis Radiochemical Yields with 125 I: (57-58.5%) with high Specific Activity
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 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]
153 Sm-EDTMP [Quadramet] 99m Tc-MDP 153 Sm-EDTMP N N PO 3 H 2 PO 3 H 2 PO 3 H 2 PO 3 H 2 153 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
Nearly 100% blood supply of a liver tumor comes from hepatic artery
Effective treatment with minimal toxicity
Average diameter of microspheres - 20 -30 m
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
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)
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 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 Interdisciplinary Research
Radiopharmaceutical Chemistry (Organic/Inorganic)
Actinide Chemistry (Inorganic)
University of Missouri Research Reactor
Radioisotope Production (medical and biological isotopes)
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
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