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

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. © 2013 Royal Society of Chemistry

Keywords

Indoles, Enzyme inhibitors, Apoptosis, Cell killing, Indoles, In vivo, Fluorine 18, Positron computed tomography

Citation

Krause-Heuer, A. M., Howell, N. R., Matesic, L., Dhand, G., Young, E. L., Burgess, L. Jiang, C. D., Lengkeek, N. A., Fookes, C. J. R., Pham, T. Q., Sobrio, F., Greguric, I & Fraser, B. H. (2013). A new class of fluorinated 5-pyrrolidinylsulfonyl isatin caspase inhibitors for PET imaging of apoptosis. MedChemComm, 4(2), 347-352. doi:10.1039/C2MD20249B