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“Graduate Studies in Radiochemistry at University of Missouri”. Susan Z. Lever Biomedical Program Director, MURR Associate Professor of Chemistry. Highest concentration of “radiochemistry” research scientists on any campus Breadth and diversity of research topics

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Graduate studies in radiochemistry at university of missouri l.jpg

“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 l.jpg

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:


Things to know about mu 2 l.jpg

Highest flux research reactor of any US campus scientists on any 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:


Radiopharmaceutical science program at mu l.jpg
Radiopharmaceutical Science Program at MU scientists on any campus

Chemistry

Biochemistry

MURR

Veterinary

Medicine

Radiology

Internal

Medicine


Things to know about mu 3 l.jpg

Long history of radiopharmaceutical development scientists on any campus

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:


Ceretec a neutral tc 99m complex l.jpg
Ceretec - a Neutral Tc-99m Complex scientists on any campus

  • 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 scientists on any campus

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.


Bifunctional chelate approach for labeling peptides proteins and antibodies with tc l.jpg

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.


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Approaches to radiolabeling reaction with technetium.

diprenorphine with radioiodine

Diprenorphine


Radioiodination via vinylstannylated alkylating agents l.jpg
Radioiodination reaction with technetium.via vinylstannylatedalkylating agents

J. L. Musachio and J. R. Lever, Tetrahedron Lett., 30, 3613-3616 (1989)


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C6-O-iodoallyl-diprenorphine for reaction with technetium.in vivo studies of opioid receptors

O-IA-DPN

Lever et al., Synapse 29: 172-182, 1998.


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Radiosynthesis of reaction with technetium.[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)


123 i o ia dpn allows ex vivo autoradiographic localization of opioid receptors in mouse brain 1 hr l.jpg
[ reaction with technetium.123I]-O-IA-DPN Allows Ex Vivo AutoradiographicLocalization of Opioid Receptors in Mouse Brain (1 hr)

Saline Control Naltrexone Block


Sa4503 fesa4503 and initial analogs l.jpg

I reaction with technetium.

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.


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Synthetic Scheme for Iodoallyl Analogs reaction with technetium.


In vitro binding affinity ic 50 nm of z and e iodoallyl analogs of sa4503 l.jpg
In Vitro Binding Affinity reaction with technetium.(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


  • Radiochemical synthesis l.jpg
    Radiochemical Synthesis reaction with technetium.

    Radiochemical Yields with 125I:

    (57-58.5%) with high

    Specific Activity


    Slide20 l.jpg

    Biodistribution of reaction with technetium.125I-Iodoallyl Analogs of SA4503 in normal mice:

    Whole Brain

    Whole brain:

    Control and Blocked


    Slide21 l.jpg

    Question: reaction with technetium.So, is there a chemical way to:

    1) Decrease Lipophilicity and Retain Affinity?


    Slide22 l.jpg

    New Iodoallyl analogs: reaction with technetium.


    Slide23 l.jpg

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


    Slide24 l.jpg

    In vivo reaction with technetium. performance of “New and Improved”

    Trans IA-Sigma Ligand

    Test drugs i.v. at 2.5 mol / kg. Values are means ± SD; n = 4.


    Slide26 l.jpg

    Radiopharmaceutical Chemistry reaction with technetium.

    also deals with Radiotherapy


    Features of murr l.jpg

    Highest neutron flux of any U.S. university reactor reaction with technetium.

    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


    Slide28 l.jpg

    The Blue Glow reaction with technetium.


    Selected isotopes currently supplied by murr l.jpg

    Lanthanides [all M reaction with technetium.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

    Selected IsotopesCurrently Supplied by MURR


    Slide30 l.jpg

    Isotope reaction with technetium.

    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


    Slide31 l.jpg

    PO reaction with technetium.

    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


    Story of quadramet tm l.jpg

    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


    Yttrium 90 microspheres l.jpg

    Nearly 100% blood supply of a liver tumor comes from hepatic artery

    Effective treatment with minimal toxicity

    Outpatient procedure

    Yttrium-90 Microspheres


    Yttrium 90 microspheres34 l.jpg

    Average diameter of microspheres - 20 -30 arterymm

    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


    Preparation of active microspheres l.jpg

    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


    Yttrium 90 microspheres36 l.jpg

    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


    Yttrium 90 microspheres become therasphere l.jpg

    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®


    Center for single photon emitting cancer imaging agents l.jpg

    Five year grant award Humanitarian Device Exemption by the U.S. Food and Drug Administration as an alternative to chemotherapy in inoperable cases 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


    Departmental research interests l.jpg
    Departmental Research Interests Humanitarian Device Exemption by the U.S. Food and Drug Administration as an alternative to chemotherapy in inoperable cases

    Radiochemistry

    Analytical

    Environmental

    Interdisciplinary

    Research

    Inorganic

    Physical

    Materials

    Organic


    Slide40 l.jpg

    Radiochemistry Program Humanitarian Device Exemption by the U.S. Food and Drug Administration as an alternative to chemotherapy in inoperable cases

    • 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


    Slide41 l.jpg

    Jurisson Group Research Humanitarian Device Exemption by the U.S. Food and Drug Administration as an alternative to chemotherapy in inoperable cases

    • Radiopharmaceutical Chemistry

      • Inorganic Chemistry

        • Tc, Re, Rh, Au, Ln

        • Ligand design

      • Radiochemistry

      • Biochemistry/Biology

    • Radioenvironmental Chemistry


    Research in the duval group l.jpg
    Research in the Duval Group Humanitarian Device Exemption by the U.S. Food and Drug Administration as an alternative to chemotherapy in inoperable cases

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


    Slide43 l.jpg

    J. David Robertson Humanitarian Device Exemption by the U.S. Food and Drug Administration as an alternative to chemotherapy in inoperable cases

    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 l.jpg
    MURR Archaeometry Lab Humanitarian Device Exemption by the U.S. Food and Drug Administration as an alternative to chemotherapy in inoperable cases

    • 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


    Slide45 l.jpg


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

    Population-Based Studies: institutions or museums in 46 statesCancer 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


    Slide47 l.jpg

    http://www.smartdraw.com/ institutions or museums in 46 states


    Things to know about mu 4 l.jpg

    Active Graduate Student Organization institutions or museums in 46 states

    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:


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