Graduate Studies in Radiochemistry at University of Missouri

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

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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

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

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Ceretec - a Neutral Tc-99m Complex

• Ceretec is used for the diagnosis of
  abnormalities of regional cerebral blood flow
• Epilepsy
• Alzheimer's Disease

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Blood Flow during Meditation
Andrew Newberg, University of Pennsylvania http/
/www.andrewnewberg.com/ accessed 6/21/05
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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.
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Bifunctional Chelate Approach for
LabelingPeptides, Proteins and Antibodies with Tc
Step 1.
Step 2.

• Presence of the N-Methyl group yields charged
  complexes upon reaction with technetium.

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Approaches to radiolabeling diprenorphine with
radioiodine
Diprenorphine
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Radioiodination via vinylstannylatedalkylating
agents
J. L. Musachio and J. R. Lever, Tetrahedron
Lett., 30, 3613-3616 (1989)
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C6-O-iodoallyl-diprenorphine forin vivo studies
of opioid receptors
O-IA-DPN
Lever et al., Synapse 29 172-182, 1998.
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Radiosynthesis of125/123I-O-IA-DPN
125I-O-IA-DPN 70 - 80 Radiochemical Yield 1200
- 1700 mCi /??mol 123I-O-IA-DPN 58 - 84
Radiochemical Yield gt 2400 mCi /??mol 2 Hours
Total Time
1. NaI125/123 MeOH / HOAc (955) Chloramine-T, 2
min. 2. HPLC / Solid Phase Extraction 3.
Formulation / QC (5 EtOH /saline)
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123I-O-IA-DPN Allows Ex Vivo AutoradiographicLo
calization of Opioid Receptors in Mouse Brain (1
hr)
Saline Control Naltrexone Block
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SA4503, FESA4503 and Initial Analogs
E - iodoallyl
SA4503 R 11CH3 FESA4503 R 18FCH2CH2-
R
Z - iodoallyl
Elsinga et al., Synapse 43259-267,
2002. Ishiwata et al., Nucl. Med. Biol.
30273-284, 2003.
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Synthetic Scheme for Iodoallyl Analogs
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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 306271-279,
1996. b Elsinga et al, Synapse 43259-267, 2002.
c n4, Mean SEM
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Radiochemical Synthesis
Radiochemical Yields with 125I (57-58.5)
with high Specific Activity
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Biodistribution of 125I-Iodoallyl Analogs of
SA4503 in normal mice
Whole Brain
Whole brain Control and Blocked
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Question So, is there a chemical way to 1)
Decrease Lipophilicity and Retain Affinity?
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New Iodoallyl analogs
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Biodistribution of New and Improved E
125I-Iodoallyl Analog in normal mice
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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.
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Radiopharmaceutical Chemistry also deals with
Radiotherapy
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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

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The Blue Glow
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Selected IsotopesCurrently Supplied by MURR

• 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

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Nuclear Properties of Various M3 Radionuclides
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153Sm-EDTMP Quadramet
99mTc-MDP
153Sm-EDTMP
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Story of QuadraMetTM

• Sm-153 identified as a useful nuclide for
  radiotherapy by MU researchers
• Development began in early 1980s 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 1980s, 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

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Yttrium-90 Microspheres

• Nearly 100 blood supply of a liver tumor comes
  from hepatic artery
• Effective treatment with minimal toxicity
• Outpatient procedure

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Yttrium-90 Microspheres

• 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

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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 b- emitter (64.2 hr half-life,
  average distance in tissue 2.5 mm)

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Yttrium-90 Microspheres

• 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

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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

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Centerfor Single Photon-EmittingCancer 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.

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

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Jurisson Group Research

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

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Research in the Duval Group
Probes new coordination environments of actinides
that bridge non-aqueous complexes with
traditional systems found under environmental
conditions.
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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 Alzheimers disease Aging the
plaques and tangles in Alzheimers disease Using
red ochre for provenance studies Evaluating
childrens chronic exposure to As and Cr from
Cu/Cr/As treated wood structures.
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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

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• 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

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Epidemiological studies have associatedlow
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.

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http//www.smartdraw.com/
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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

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