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.
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.
