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The proto-oncogenes NTRK1/2/3 encode the tropomyosin receptor kinases TrkA/B/C which play pivotal roles in neurobiology and cancer. We describe herein the discovery of [11C]-(R)-3 ([11C]-(R)-IPMICF16), a first-in-class positron emission tomography (PET) TrkB/C-targeting radiolabeled kinase inhibitor lead. Relying on extensive human kinome vetting, we show that (R)-3 is the most potent and most selective TrkB/C inhibitor characterized to date. It is demonstrated that [11C]-(R)-3 readily crosses the blood-brain barrier (BBB) in rodents and selectively binds to TrkB/C receptors in vivo, as evidenced by entrectinib blocking studies. Substantial TrkB/C-specific binding in human brain tissue is observed in vitro, with specific reduction in the hippocampus of Alzheimer's disease (AD) versus healthy brains. We additionally provide preliminary translational data regarding the brain disposition of [11C]-(R)-3 in primates including first-in-human assessment. These results illustrate for the first time the use of a kinome-wide selective radioactive chemical probe for endogenous kinase PET neuroimaging in human. [ABSTRACT FROM AUTHOR]

4-[18F]Fluoro-m-hydroxyphenethylguanidine([18F]4F-MHPG, [18F]1) is a newcardiac sympathetic nerve radiotracer with kinetic properties favorablefor quantifying regional nerve density with PET and tracer kineticanalysis. An automated synthesis of [18F]1was developed in which the intermediate 4-[18F]fluoro-m-tyramine ([18F]16) was preparedusing a diaryliodonium salt precursor for nucleophilic aromatic [18F]fluorination. In PET imaging studies in rhesus macaquemonkeys, [18F]1demonstrated high qualitycardiac images with low uptake in lungs and the liver. Compartmentalmodeling of [18F]1kinetics provided net uptakerate constants Ki(mL/min/g wet), andPatlak graphical analysis of [18F]1kineticsprovided Patlak slopes Kp(mL/min/g).In pharmacological blocking studies with the norepinephrine transporterinhibitor desipramine (DMI), each of these quantitative measures declinedin a dose-dependent manner with increasing DMI doses. These initialresults strongly suggest that [18F]1can providequantitative measures of regional cardiac sympathetic nerve densityin human hearts using PET. [ABSTRACT FROM AUTHOR]