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“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: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: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
ChemistryChemistry
BiochemistryBiochemistry
Veterinary Veterinary MedicineMedicine RadiologyRadiology
Internal Internal MedicineMedicine
MURRMURR
Things to know about MU #3: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
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-LigandConjugate
OrganicLinker
Biomolecule
TumorCellReceptor
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
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.
O
CH3O
HO
CH3CH3
OH
N
Approaches to radiolabelingdiprenorphine with radioiodine
Diprenorphine
Radioiodination via vinylstannylatedalkylating agents
OTs
OTs
Nuc
Nuc
I* Nuc
I*
Nuc
I* = 127I, 125I, 123I
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)
Lever et al., Synapse 29: 172-182, 1998.
C6-O-iodoallyl-diprenorphine forin vivo studies of opioid receptors
CH3
CH3
HO
O
HO
N
O*I
I* = I127
, I125
, I123
O-IA-DPN
Radiosynthesis of[125/123I]-O-IA-DPN
CH3CH3
HO
O
HO
N
O
n-Bu3Sn
O
HO
N
O
*ICH3
CH3
HO
1. NaI125/123
MeOH / HOAc (95:5)Chloramine-T, 2 min.
2. HPLC / Solid PhaseExtraction
3. Formulation / QC(5% EtOH /saline)
[125I]-O-IA-DPN70 - 80% Radiochemical Yield
1200 - 1700 mCi /mol
[123I]-O-IA-DPN58 - 84% Radiochemical Yield
> 2400 mCi /mol2 Hours Total Time
[125I]-O-IA-DPN70 - 80% Radiochemical Yield
1200 - 1700 mCi /mol
[123I]-O-IA-DPN58 - 84% Radiochemical Yield
> 2400 mCi /mol2 Hours Total Time
[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
Elsinga et al., Synapse 43:259-267, 2002.Ishiwata et al., Nucl. Med. Biol. 30:273-284, 2003.
SA4503; R = 11CH3
FESA4503; R = 18FCH2CH2-
R = I
I
E - iodoallyl
Z - iodoallyl
N
N OCH3
OCH3
Synthetic Scheme for Iodoallyl Analogs
R1=H, R2=n-Bu3Sn, 3ZR1=n-Bu3Sn, R2=H, 3E
HO AHO R1
R2B
TsO R1
R2
NN OCH3
O R1
R2
Scheme 1b. Reagents: A, propargyl alcohol/ tri-n-butyltin hydride. B, potassium trimethylsilanolate/ tosylate chloride. C, 4-O-demethyl SA4503. D, iodine.
Scheme 1b
D
NN OCH3
O R1
R2
1 23
4
5
R1=H, R2=n-Bu3Sn, 4ZR1=n-Bu3Sn, R2=H, 4E
R1=H, R2=I, 5ZR1=I, R2=H, 5E
C
+ TsOn-Bu3Sn
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
Radiochemical Synthesis
NN OCH3
OH
OTsR1
R2
NN OCH3
O R1
I2
R2
NN OCH3
O R4
R3
R1=H, R2=n-Bu3Sn, 1ZR1=n-Bu3Sn, R2=H, 1E
R1=H, R2=n-Bu3Sn, 2ZR1=n-Bu3Sn, R2=H, 2E
R1=H, R2=I, 3ZR1=I, R2=H, 3E
Radiochemical Yields with 125I:
(57-58.5%) with highSpecific Activity
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 of Biodistribution of 125I-Iodoallyl Analogs I-Iodoallyl Analogs of SA4503 in normal mice:of SA4503 in normal mice:
0.0
0.2
0.4
0.6
0.8
%ID / gWhole Brain
30 min 60 min
p = 0.03
*
Whole brain:Whole brain:Control and BlockedControl and Blocked
Whole BrainWhole Brain
Question: So, is there a chemical way to:1) Decrease Lipophilicity and Retain Affinity?
N
N OCH3
OCH3
I
N
N OCH3
O I
NN OCH3
OCH3
I
NN OCH3
OCH3
I
Z-IA-DM-PE-PIPZ Ki 1 19.9 ± 1.3 nM; 2 455 ± 66
nM (n = 4) 2 / 1 = 23
[125I] -Z-IA-DM-PE-PIPZ Log D7.4 = 2.27 ± 0.006 (n = 5)
E-IA-DM-PE-PIPZ Ki 1 15.1 ± 1.3 nM; 2 1263 ± 166
nM (n = 4) 2 / 1 = 84
[125I] -E-IA-DM-PE-PIPZ Log D7.4 = 2.25 ± 0.008 (n = 5)
New Iodoallyl analogs:
Biodistribution of “New and Improved” Biodistribution of “New and Improved” EE 125I-I-Iodoallyl Analog in normal mice:Iodoallyl Analog in normal mice:
I-125 IA-Sigma CompoundsWhole Brain Comparison at 60 min
(n = 4, means +/- SD )
E-1 E-1 Haldol E-2 E-2 Haldol Z-2 Z-2 Haldol0
1
2
3
%ID / gWhole Brain
Haldol (2.5 / )mol kg
*
**p = 0.03
p < 0.0001
**p < 0.0001
0.5 1.5 2.5 3.5 4.5
Cerebellum
Hypothalamus
Striatum
Frontal Cortex
Pons / Medulla
Colliculi
Saline ControlCold Compound
%ID / g Tissue (60 min)
Haldol (σ1/σ2)1063(BD σ1)- (Br Machσ2)
***
* ,ANOVA Dunnett'sp<0.01
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 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
Nuclear Properties of Various M3+ Radionuclides
Isotope Half-Life Decay Ave Range Approx. Range
(days) - (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
153153Sm-EDTMP [Quadramet]Sm-EDTMP [Quadramet] 99m99mTc-MDPTc-MDP 153153Sm-EDTMPSm-EDTMP
NN
PO 3H 2
PO 3H 2
PO 3H 2
PO 3H 2
153153SmSm
+
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
Yttrium-90 Microspheres
Nearly 100% blood supply of a liver tumor comes from hepatic artery
Effective treatment with minimal toxicityOutpatient procedure
Yttrium-90 Microspheres
Average diameter of microspheres - 20 -30 mYttrium is an integral part of the glass matrixDelbert 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
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
Centerfor Single Photon-Emitting
Cancer Imaging AgentsFive 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
AnalyticalAnalytical
InorganicInorganic
OrganicOrganic
PhysicalPhysical
EnvironmentalEnvironmental
MaterialsMaterials
RadiochemistryRadiochemistry
InterdisciplinaryInterdisciplinaryResearchResearch
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
Jurisson Group ResearchJurisson Group Research
Radiopharmaceutical Chemistry• Inorganic Chemistry
• Tc, Re, Rh, Au, Ln
• Ligand design
• Radiochemistry
• Biochemistry/Biology
Radioenvironmental Chemistry
Research in the Duval Group
UU
U
U
U
U
O
OO
O
O
O
O
O
O
OO
O
OCp‡
Cp‡
Cp‡
Cp‡
N N
N N
Fe
U
O
O
U
O
ON
N
R
L
L
L
LN
NN
N
RuL
LL
U
O
O
L
L
R
N N
N N
M
HN
NH
Mes
Mes
Mes
U
O
O
O
O
O
O
4-
N
N
O
N
R
RR
U
N
OU
O
O
N
N
R
N
R
NR
2-
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 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.
http://www.smartdraw.com/
Things to know about MU #4: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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