The unbound fraction from the brain extraction studies was analyzed. With

The unbound fraction in the brain extraction studies was analyzed. With extractable brain radioactivity of only two (Fig. 4a), the transfer of polar metabolites across the blood-brain barrier as well as the prospective involvement of [11C]PF-04457845 in other metabolic pathways apart from FAAH within the CNS are each nominal. A equivalent metabolic evaluation was observed for [11C]CURB [20]. When the outcomes from metabolic analysis are combined using the observed higher specificity and selectivity, the likelihood is extremely high that the observed radioactivity uptake in to the rat brain is principally attributable to binding of [11C]PF-04457845 to FAAH.NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript5. ConclusionThe breadth of clinical information for PF-04457845 made it an appealing candidate as a PET radiotracer and led us to pursue the radiosynthesis of [11C]PF-04457845. Results from ex vivo rat research demonstrated high brain uptake of this radiotracer which binds selectively, specifically, and irreversibly to FAAH devoid of troublesome brain-penetrant metabolites. The differentiation among regions of high and low FAAH expression along with the subsequent reduction in uptake across all regions upon pharmacological blockade both suggest the kinetics are favorable for in vivo imaging. The facile radiosynthesis of [11C]PF-04457845, encouraging preclinical final results and known security data of PF-04457845 warrant further evaluation of this radiotracer in higher species.AcknowledgmentsThis perform was supported by NIH Grant # 1R21MH094424-01 to AAW, an Ontario Ministry of Investigation and Improvement Early Researcher award to NV, as well as a University of Toronto Institute of Healthcare Science Open Fellowship award to JWH. We would prefer to thank Armando Garcia, Winston Stableford, Min Wong, Virginia S. Wilson, Patrick McCormick, and Alvina Ng for their help together with the radiochemistry and animal dissection experiments.Nucl Med Biol. Author manuscript; offered in PMC 2014 August 01.Hicks et al.Web page
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