Synthesis and biological evaluation of fluorine-18 labeled RS-15385-197 analogs: Potent and selective alpha-2 adrenergic receptor radioligands for PET

Aberrations in the {alpha}{sub 2}-adrenergic receptor system have been implicated in a number of disease states including hypertension, drug abuse, depression, and neurodegenerative disorders such as Alzheimer`s Disease. RS-15385-FP (1) and RS-15385-FPh (2) are analogs of the {alpha}{sub 2}-adrenergic receptor antagonist RS- 15385-197 which display a high receptor binding affinity (K{sub i} = 0.2 and 0.5 nM, respectively) as well as a high degree of {alpha}{sub 2}/{alpha}{sub 1} selectivity (7000:1 and 2000:1, respectively). We synthesized [F-18]-2 was synthesized by fluoro-for-nitro exchange on the corresponding nitrophenyl derivative which was produced in two steps from the hydroxypropyl sulfonamide. In vivo distribution studies in rats and PET studies in monkeys demonstrate uptake in {alpha}{sub 2}-adrenergic receptor rich regions of the brain, particularly the locus coeruleus.