“Graduate Studies in
Radiochemistry at
University of Missouri”
Susan Z. Lever
Biomedical Program Director, MURR
Associate ...
Things to know about MU #1:
• Highest concentration of “radiochemistry” research
scientists on any campus
– Breadth and di...
Things to know about MU #2:
• Highest flux research reactor of any US campus
• High field nmrs, with an 800 MHz on order
•...
Radiopharmaceutical Science Program at MU
ChemistryChemistry
BiochemistryBiochemistry
VeterinaryVeterinary
MedicineMedicin...
Things to know about MU #3:
• Long history of radiopharmaceutical development
• Established program in archeometry
• World...
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
Link...
Bifunctional Chelate ApproachBifunctional Chelate Approach for
Labeling
Peptides, Proteins and Antibodies with Tc
• Presen...
O
CH3O
HO
CH3CH3
OH
N
Approaches to radiolabeling
diprenorphine with radioiodine
Diprenorphine
Radioiodination via vinylstannylated
alkylating agents
OTs
OTs
Nuc
Nuc
I*
Nuc
I*
Nuc
I* = 127
I, 125
I, 123
I
I*
(n-Bu)3Sn...
Lever et al., Synapse 29: 172-182, 1998.
C6-O-iodoallyl-diprenorphine for
in vivo studies of opioid receptors
CH3
CH3
HO
O...
Radiosynthesis of
[125/123
I]-O-IA-DPN
CH3
CH3
HO
O
HO
N
O
n-Bu3Sn
O
HO
N
O
*I
CH3
CH3
HO
1. NaI125/123
MeOH / HOAc (95:5)...
[123
I]-O-IA-DPN Allows Ex Vivo Autoradiographic
Localization of Opioid Receptors in Mouse Brain (1
hr)
Saline Control Nal...
SA4503, FESA4503 and Initial
Analogs
Elsinga et al., Synapse 43:259-267, 2002.
Ishiwata et al., Nucl. Med. Biol. 30:273-28...
Synthetic Scheme for Iodoallyl
Analogs
R1=H,R2=n-Bu3Sn, 3Z
R1=n-Bu3Sn, R2=H, 3E
HO A
HO R1
R2
B
TsO R1
R2
N
N OCH3
O R1
R2...
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...
Radiochemical
Synthesis
N
N OCH3
OH
OTsR1
R2
N
N OCH3
O R1
I2
R2
N
N OCH3
O R4
R3
R1=H, R2=n-Bu3Sn, 1Z
R1=n-Bu3Sn, R2=H, 1...
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Whole Brain
%ID / g
0 30 60 90 120
Time (min)
Z-IA-SA4503
E-IA-SA4503
(means +/- SD; n...
Question: So, is there a chemical way to:
1) Decrease Lipophilicity and Retain Affinity?
N
N OCH3
OCH3
I
N
N OCH3
O I
N
N OCH3
OCH3
I
N
N OCH3
OCH3
I
Z-IA-DM-PE-PIPZ
Ki 1 19.9 ± 1.3 nM; 2 455 ± 66
nM (n = 4)
2 / 1 = 23
[125
I]-Z-IA-DM-PE-PI...
Biodistribution of “New and Improved”Biodistribution of “New and Improved” EE 125
I-I-
Iodoallyl Analog in normal mice:Iod...
0.5 1.5 2.5 3.5 4.5
Cerebellum
Hypothalamus
Striatum
Frontal Cortex
Pons / Medulla
Colliculi
Saline Control
Cold Compound
...
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...
The Blue Glow
Selected Isotopes
Currently Supplied by MURR
• Lanthanides [all M3+
]
– Pm-149, Sm-153, Ho-166, Dy-166, Lu-177
• Transitio...
Nuclear Properties of Various M3+
Radionuclides
Isotope Half-Life Decay Ave Range Approx. Range
(days) β - (MeV) (mm water...
153153
Sm-EDTMP [Quadramet]Sm-EDTMP [Quadramet]
99m99m
Tc-MDPTc-MDP 153153
Sm-EDTMPSm-EDTMP
N
N
PO 3H2
PO 3H2
PO 3H2
PO 3H...
Story of QuadraMetTM
• Sm-153 identified as a useful nuclide for radiotherapy by
MU researchers
• Development began in ear...
Yttrium-90 Microspheres
Nearly 100% blood supply of a liver tumor comes
from hepatic artery
Effective treatment with minim...
Yttrium-90
Microspheres
Average diameter of microspheres - 20 -30 µm
Yttrium is an integral part of the glass matrix
Delbe...
Preparation of Active
Microspheres
Y-89 microspheres are irradiated in the MU-
Research Reactor (MURR), resulting in the
c...
Yttrium-90 Microspheres
In a recent study (Dancy et al., J. Nucl. Med. 41: 1673-
1681, 2000), patients with hepatocellular...
Yttrium-90 Microspheres become
TheraSphere®
March, 2000: MDS Nordion (Kanata, Ont.
Canada) was granted a Humanitarian Devi...
Center
for Single Photon-Emitting
Cancer Imaging Agents
Five year grant award from the National Cancer
Institute of the N...
Departmental Research Interests
AnalyticalAnalytical
InorganicInorganic
OrganicOrganic
PhysicalPhysical
EnvironmentalEnvir...
Radiochemistry ProgramRadiochemistry Program
• Chemistry Department
• Radiopharmaceutical Chemistry (Organic/Inorganic)
• ...
Jurisson Group ResearchJurisson Group Research
Radiopharmaceutical
Chemistry
• Inorganic Chemistry
• Tc, Re, Rh, Au, Ln
• ...
Research in the Duval Group
U
U
U
U
U
U
O
OO
O
O
O
O
O
O
O
O
O
O
Cp‡
Cp‡
Cp‡
Cp‡
N N
N N
Fe
U
O
O
U
O
O
N
N
R
L
L
L
L
N
N
...
J. David Robertson
Using the unique properties of the nucleus to study
chemical processes/problems which, frequently, cann...
MURR Archaeometry Lab
NAA became the preeminent technique in
archaeometric materials analysis following
the pioneering wor...
• Collaborative projects with US archaeologists at academic
institutions or museums in 46 states
• Service to cultural res...
Epidemiological studies have associated
low selenium intake with increased cancer
risk• Population-Based Studies: Cancer i...
http://www.smartdraw.com/
Things to know about MU #4:
• Active Graduate Student Organization
• Geographically south of the glaciated till plain, so ...
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  • The development Quadramet exemplifies the translational research capabilities at MU: from the and production of the radioisotope (Sm-153) and the identification of the phosphonate compound, (EDTMP) which targets bone cancer to the initial clinical trials in human patients.
  • In this slide the three basic designs used in trace-element epidemiology studies are defined. Examples are given on subsequent slides.
  • image is everything

    1. 1. “Graduate Studies in Radiochemistry at University of Missouri” Susan Z. Lever Biomedical Program Director, MURR Associate Professor of Chemistry
    2. 2. 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
    3. 3. 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
    4. 4. Radiopharmaceutical Science Program at MU ChemistryChemistry BiochemistryBiochemistry VeterinaryVeterinary MedicineMedicine RadiologyRadiology InternalInternal MedicineMedicine MURRMURR
    5. 5. 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
    6. 6. Ceretec - a Neutral Tc-99m Complex • Ceretec is used for the diagnosis of abnormalities of regional cerebral blood flow • Epilepsy • Alzheimer's Disease
    7. 7. Andrew Newberg, University of Pennsylvania http://www.andrewnewberg.com/ accessed 6/21/05 Blood Flow during Meditation
    8. 8. Design, synthesis and evaluation of novel biological targets for diagnosis and therapy Metal-Ligand Conjugate Organic Linker Biomolecule Tumor CellReceptor N S N SH O 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
    9. 9. Bifunctional Chelate ApproachBifunctional Chelate Approach for Labeling Peptides, Proteins and Antibodies with Tc • Presence of the N-Methyl group yields charged complexes upon reaction with technetium. N S N SH O NH2 NN SH NH O HS NN NH O S S Tc O Step 1. Step 2.
    10. 10. O CH3O HO CH3CH3 OH N Approaches to radiolabeling diprenorphine with radioiodine Diprenorphine
    11. 11. Radioiodination via vinylstannylated alkylating agents OTs OTs Nuc Nuc I* Nuc I* Nuc I* = 127 I, 125 I, 123 I I* (n-Bu)3Sn (n-Bu)3Sn Nuc: (n-Bu)3Sn (n-Bu)3Sn E Z J. L. Musachio and J. R. Lever, Tetrahedron Lett., 30, 3613-3616 (1989)
    12. 12. Lever et al., Synapse 29: 172-182, 1998. C6-O-iodoallyl-diprenorphine for in vivo studies of opioid receptors CH3 CH3 HO O HO N O*I I* = I 127 , I 125 , I 123 O-IA-DPN
    13. 13. Radiosynthesis of [125/123 I]-O-IA-DPN CH3 CH3 HO O HO N O n-Bu3Sn O HO N O *I CH3 CH3 HO 1. NaI125/123 MeOH / HOAc (95:5) Chloramine-T, 2 min. 2. HPLC / Solid Phase Extraction 3. Formulation / QC (5% EtOH /saline) [125 I]-O-IA-DPN 70 - 80% Radiochemical Yield 1200 - 1700 mCi / µmol [123 I]-O-IA-DPN 58 - 84% Radiochemical Yield > 2400 mCi / µmol 2 Hours Total Time [125 I]-O-IA-DPN 70 - 80% Radiochemical Yield 1200 - 1700 mCi / µmol [123 I]-O-IA-DPN 58 - 84% Radiochemical Yield > 2400 mCi / µmol 2 Hours Total Time
    14. 14. [123 I]-O-IA-DPN Allows Ex Vivo Autoradiographic Localization of Opioid Receptors in Mouse Brain (1 hr) Saline Control Naltrexone Block
    15. 15. 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 CH3 FESA4503; R = 18 FCH2CH2- R = I I E - iodoallyl Z - iodoallyl N N OCH3 OCH3
    16. 16. Synthetic Scheme for Iodoallyl Analogs R1=H,R2=n-Bu3Sn, 3Z R1=n-Bu3Sn, R2=H, 3E HO A HO R1 R2 B TsO R1 R2 N N OCH3 O R1 R2 Scheme1b. Reagents: A, propargyl alcohol/ tri-n-butyltinhydride. B, potassium trimethylsilanolate/ tosylate chloride. C, 4-O-demethyl SA4503. D, iodine. Scheme1b D N N OCH3 O R1 R2 1 2 3 4 5 R1=H, R2=n-Bu3Sn, 4Z R1=n-Bu3Sn,R2=H, 4E R1=H, R2=I, 5Z R1=I, R2=H, 5E C + TsO n-Bu3Sn
    17. 17. 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
    18. 18. Radiochemical Synthesis N N OCH3 OH OTsR1 R2 N N OCH3 O R1 I2 R2 N N OCH3 O R4 R3 R1=H, R2=n-Bu3Sn, 1Z R1=n-Bu3Sn, R2=H, 1E R1=H, R2=n-Bu3Sn, 2Z R1=n-Bu3Sn, R2=H, 2E R1=H, R2=I, 3Z R1=I, R2=H, 3E Radiochemical Yields with 125 I: (57-58.5%) with high Specific Activity
    19. 19. 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 Whole Brain %ID / g 0 30 60 90 120 Time (min) Z-IA-SA4503 E-IA-SA4503 (means +/- SD; n = 4-5) Biodistribution ofBiodistribution of 125 I-Iodoallyl AnalogsI-Iodoallyl Analogs of SA4503 in normal mice:of SA4503 in normal mice: 0.0 0.2 0.4 0.6 0.8 %ID / g Whole Brain 30 min 60 min p = 0.03 * Whole brain:Whole brain: Control and BlockedControl and Blocked Whole BrainWhole Brain
    20. 20. Question: So, is there a chemical way to: 1) Decrease Lipophilicity and Retain Affinity? N N OCH3 OCH3 I N N OCH3 O I
    21. 21. N N OCH3 OCH3 I N N OCH3 OCH3 I Z-IA-DM-PE-PIPZ Ki 1 19.9 ± 1.3 nM; 2 455 ± 66 nM (n = 4) 2 / 1 = 23 [125 I]-Z-IA-DM-PE-PIPZ Log D7.4 = 2.27± 0.006(n = 5) E-IA-DM-PE-PIPZ Ki 1 15.1 ± 1.3nM; 2 1263± 166 nM (n = 4) 2 / 1 = 84 [125 I]-E-IA-DM-PE-PIPZ Log D7.4 = 2.25± 0.008(n = 5) New Iodoallyl analogs:
    22. 22. Biodistribution of “New and Improved”Biodistribution of “New and Improved” EE 125 I-I- Iodoallyl Analog in normal mice:Iodoallyl Analog in normal mice: I-125 IA-Sigma Compounds Whole Brain Comparison at 60 min (n = 4, means +/- SD ) E-1 E-1 Haldol E-2 E-2 Haldol Z-2 Z-2 Haldol 0 1 2 3 %ID / g Whole Brain Haldol (2.5µµολ / κγ) ∗ ∗∗ p = 0.03 p < 0.0001 ** p < 0.0001
    23. 23. 0.5 1.5 2.5 3.5 4.5 Cerebellum Hypothalamus Striatum Frontal Cortex Pons / Medulla Colliculi Saline Control Cold Compound %ID / g Tissue (60 min) Haldol (σ1/σ2) Β∆1063 (σ1) Βρ−Μαχη (σ2) ∗ ∗ ∗ ∗ ΑΝΟςΑ, ∆υννεττ∋σ π< 0.01 Test drugs i.v. at 2.5 µmol / kg. Values are means ± SD; n = 4. In vivo performance of “New and Improved” Trans IA-Sigma Ligand
    24. 24. Radiopharmaceutical Chemistry also deals with Radiotherapy
    25. 25. 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
    26. 26. The Blue Glow
    27. 27. Selected Isotopes Currently 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
    28. 28. Nuclear Properties of Various M3+ Radionuclides Isotope Half-Life Decay Ave Range Approx. Range (days) β - (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
    29. 29. 153153 Sm-EDTMP [Quadramet]Sm-EDTMP [Quadramet] 99m99m Tc-MDPTc-MDP 153153 Sm-EDTMPSm-EDTMP N N PO 3H2 PO 3H2 PO 3H2 PO 3H2 153153 SmSm +
    30. 30. Story of QuadraMetTM • 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
    31. 31. Yttrium-90 Microspheres Nearly 100% blood supply of a liver tumor comes from hepatic artery Effective treatment with minimal toxicity Outpatient procedure
    32. 32. Yttrium-90 Microspheres Average diameter of microspheres - 20 -30 µm 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
    33. 33. 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 β- emitter (64.2 hr half-life, average distance in tissue: 2.5 mm)
    34. 34. 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
    35. 35. 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
    36. 36. 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.
    37. 37. Departmental Research Interests AnalyticalAnalytical InorganicInorganic OrganicOrganic PhysicalPhysical EnvironmentalEnvironmental MaterialsMaterials RadiochemistryRadiochemistry InterdisciplinaryInterdisciplinary ResearchResearch
    38. 38. Radiochemistry ProgramRadiochemistry 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
    39. 39. Jurisson Group ResearchJurisson Group Research Radiopharmaceutical Chemistry • Inorganic Chemistry • Tc, Re, Rh, Au, Ln • Ligand design • Radiochemistry • Biochemistry/Biology Radioenvironmental Chemistry
    40. 40. Research in the Duval Group U U U U U U O OO O O O O O O O O O O Cp‡ Cp‡ Cp‡ Cp‡ N N N N Fe U O O U O O N N R L L L L N N N N RuL L L U O O L L R N N N N M H N N H Mes Mes Mes U O O O O O O 4- N N O N R RR U N O U O O N N R N R N R 2- Probes new coordination environments of actinides that bridge non- aqueous complexes with traditional systems found under environmental conditions.
    41. 41. 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.
    42. 42. 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
    43. 43. • 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
    44. 44. 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.
    45. 45. http://www.smartdraw.com/
    46. 46. 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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