Radiotracers have enabled investigations of molecular phenomena which are at the heart of understanding human disease and developing effective treatments. Yet, there exists a major deficiency in our ability to synthesize radiotracers. The focus of the research described herein is the development of new rapid chemical methods for the incorporation of readily available carbon-11 labeled precursors into common pharmacophore moieties for their use as radiotracers. The strategies are designed to target functional groups that are not adequately addressed by existing carbon-11 incorporation strategies. A particular focus is placed on radiolabeling compounds identified in the literature as candidates for the study and treatment of psychiatric and neurological disorders, with a special emphasis on addictive disorders. Specifically, the new chemical strategies we develop will be used to radiolabel a glutamate receptor antagonist. We will then evaluate the labeled compound as a radiotracer for positron emission tomography (PET).We will accomplish this in three specific aims.
In Specific Aim 1, we will develop new rapid chemical reactions for the incorporation of carbon-11 into a) carbamate/carbonate functional groups and b) piperidine heterocycles. This will be accomplished by incorporating common [11C] labeling precursors, [11C]-carbon dioxide and [11C]-cyanide, using rapid organic synthesis. Carbonate and carbamate radiolabeling will be achieved by the direct chemical fixation of [11C]O2. Piperidine heterocycle labeling will be achieved through a novel reductive cyclization of 1,4-cyanoaldehydes prepared from [11C]N.
In Specific Aim 2, we will evaluate these chemical strategies by radiolabeling a N-methyl-D-aspartate (NMDA) receptor antagonist.
In Specific Aim 3, the radiolabeled antagonist will be evaluated as a radiotracer in vivo by PET.

Public Health Relevance

Advances in radiotracer chemistry and translational research directed to neurologicall targets involved in human brain dysfunction will accelerate the understanding of brain function and the development of effective treatments for brain disorders. The research proposed herein will advance radiotracer chemistry through the development of new methods for carbon-11 incorporation. These methods will be used for the synthesis of radiotracers to study brain dysfunction &neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32EB008320-03
Application #
7673318
Study Section
Special Emphasis Panel (ZRG1-F15-V (20))
Program Officer
Erim, Zeynep
Project Start
2007-09-30
Project End
2009-11-04
Budget Start
2009-09-30
Budget End
2009-11-04
Support Year
3
Fiscal Year
2009
Total Cost
$4,076
Indirect Cost
Name
Brookhaven National Laboratory
Department
Type
DUNS #
027579460
City
Upton
State
NY
Country
United States
Zip Code
11973
Hooker, Jacob M (2010) Modular strategies for PET imaging agents. Curr Opin Chem Biol 14:105-11
Hooker, Jacob M; Kim, Sung Won; Reibel, Achim T et al. (2010) Evaluation of [(11)C]metergoline as a PET radiotracer for 5HTR in nonhuman primates. Bioorg Med Chem 18:7739-45
Hooker, Jacob M; Kim, Sung Won; Alexoff, David et al. (2010) Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [C]MS-275 using Positron Emission Tomography. ACS Chem Neurosci 1:65-73
Hooker, Jacob M; Patel, Vinal; Kothari, Shiva et al. (2009) Metabolic changes in the rodent brain after acute administration of salvinorin A. Mol Imaging Biol 11:137-43
Hooker, Jacob M; Munro, Thomas A; Béguin, Cécile et al. (2009) Salvinorin A and derivatives: protection from metabolism does not prolong short-term, whole-brain residence. Neuropharmacology 57:386-91
Hooker, Jacob M; Reibel, Achim T; Hill, Sidney M et al. (2009) One-pot, direct incorporation of [11C]CO2 into carbamates. Angew Chem Int Ed Engl 48:3482-5
Hooker, Jacob M; Schonberger, Matthias; Schieferstein, Hanno et al. (2008) A simple, rapid method for the preparation of [11C]formaldehyde. Angew Chem Int Ed Engl 47:5989-92
Hooker, Jacob M; Xu, Youwen; Schiffer, Wynne et al. (2008) Pharmacokinetics of the potent hallucinogen, salvinorin A in primates parallels the rapid onset and short duration of effects in humans. Neuroimage 41:1044-50