Fatty Acid Amide Hydrolase (FAAH) is the enzyme responsible for hydrolysing endocannabinoids such as anandamide. As such it plays a major role in setting the tone of the cannabinoid system in the human brain. There is substantial evidence that dysfunction of FAAH biochemistry plays a major role in addiction, and psychiatric and neurological illnesses. The ability to measure the levels of FAAH in the living human brain would be extremely useful. Not only could the efficacy of potential FAAH inhibitor drugs be measured directly, but also the role of FAAH in certain populations could be compared to normal populations (e.g. drug users compared to non-users). Goals. FAAH could be measured in the human brain by positron emission tomography (PET);however, no positron-emitting radiotracers exist that are suitable for FAAH imaging. It is the specific aim of this project to design, synthesize, and develop radiotracers that cross the blood-brain barrier and then bind selectively to FAAH. Ultimately we hope to have a choice of radiotracers to measure the amounts and brain distribution of FAAH in human populations using PET. Innovation. The mechanism of inhibition of carbamate and urea inhibitors of FAAH involves attachment of the enzyme to the carbonyl carbon of the carbamate and ureas. As a consequence, successful PET imaging of FAAH will require the radiolabelling of the carbamates and ureas in the carbonyl position. Using novel and unique radiochemistry techniques, which we have recently developed, the required [carbonyl-11C] labeled carbamates and ureas will be synthesized from readily available cyclotron-produced 11CO2. The dovetailing of the radiochemistry with the specific mechanistic pathway followed by these FAAH inhibitors is a key facet of this proposal. We have already demonstrated the feasibility of this approach by radiosynthesizing and evaluating ex vivo in rats a [carbonyl-11C]carbamate analogue of the prototypical FAAH inhibitor, URB597. Methods. A series of carbamates and ureas have been chosen as candidate radiotracers, based upon their structure-affinity relationships to FAAH, their potential to cross the blood-brain barrier, and their suitability for radiolabeling. The novel radiotracers will be evaluated ex vivo in rats to determine their suitability for FAAH imaging by PET. Criteria of evaluation will include extent of brain penetration, appropriate regional biodistribution, and specificity of binding to FAAH over other proteins. Particular importance will be paid to influx and efflux rates and the rate at which FAAH binding occurs, as these are crucial aspects for successful transfer of these radiotracers from rats into human PET imaging. Outcome. Radiotracers as tools for measurement of FAAH in the living human brain using PET.
This work will develop key tools designed to advance the clinical and scientific understanding of the cannabinoid system in the living human brain. Since the cannabinoid system is a key player in pain, addiction, anxiety, and other aspects of both the healthy and disordered brain, such tools could have a significant impact on the health and welfare of the community at large.
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|Wilson, Alan A; Hicks, Justin W; Sadovski, Oleg et al. (2013) Radiosynthesis and evaluation of [¹¹C-carbonyl]-labeled carbamates as fatty acid amide hydrolase radiotracers for positron emission tomography. J Med Chem 56:201-9|
|Hicks, Justin W; Parkes, Jun; Sadovski, Oleg et al. (2013) Synthesis and preclinical evaluation of [11C-carbonyl]PF-04457845 for neuroimaging of fatty acid amide hydrolase. Nucl Med Biol 40:740-6|