The nonpeptidyl caspase binding radioligand (S)-1-(4-(2-[18F]fluoroethoxy)benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin ([18F]CbR) as potential positron emission tomography-compatible apoptosis imaging agent

Aim. Radiolabeled Annexin V-derivatives are well characterized phosphatidylserine-targeting biomarkers and considered as state-of-the-art tracers for non-invasive molecular imaging of apoptosis. In contrast to Annexin V-derived imaging agents being surrogate markers of apoptosis, activated cysteinyl aspartate-specific proteases (caspases) represent the common final path of apoptosis being a suitable in vivo target for the exclusive imaging of apoptotic tissues in vivo. Methods. We suggest 5-pyrrolidinylsulfonyl isatins; as a potential nonpeptidyl class of caspase inhibitors for the design of caspase binding radioligands (CbRs), that could be used for in vivo visualization of activated effector caspases. The caspase inhibitor (S)-(+)-5-[1-(2-Methoxymethylpyrrolidiny)suffonyl]isatin 1 (Ki, (caspare-3) (1)=60 nm) was chosen as lead structure for th development of nonpeptidyl CbRs. Its structural expansion at the NI-position the yields moderate lipophilicp-(2-fluoroethoxy)benzyl variant 2 (log D=2.2), without loss of caspase binding potency (IC50, caspase-3 (2)=36.4 nM). Results. Subsequent automated radiosynthesis of the corresponding F-18-labeled target CbR [F-18]2 was performed by direct F-18-labeling of tosylate precursor 4. Conclusion. As shown by biodistribution studies and small animal positron emission tomography a nonpeptidyl 5-pyrrolidinylsulfonyl isatin-type caspase inhibitor (S)-1-(4-(2-[F-18]Fluoroetho-xy)benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyllisatin [F-18]2 with rapid blood clearance characteristics could potentially detect apoptosis in vivo.