A new class of fluorinated 5-pyrrolidinylsulfonyl isatin caspase inhibitors for PET imaging of apoptosis

Abstract

Thirteen compounds in a new class of fluorinated 5-pyrrolidinylsulfonyl isatin derivatives were synthesised that have potent and selective inhibitory activity against effector caspases-3 and -7. With in vivo animal PET imaging studies of cerebral ischemia being planned, N-benzylation with selected para-substituted benzylic halides allowed systematic variation of lipophilicity (logP 1.94–3.31) without decreasing inhibition potency (IC₅₀). From this series the p-methoxybenzyl analogue was selected for initial ‘proof-of-concept’ [¹⁸F]-fluoride radiolabelling which proceeded in good yield and purity with no need for a protection/deprotection strategy.