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

Q J Nucl Med Mol Imaging. 2007 Mar;51(1):67-73.


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-Methoxy-methylpyrrolidinyl)sulfonyl]isatin 1 (K(i, caspase)-3 (1)=60 nM) was chosen as lead structure for the development of nonpeptidyl CbRs. Its structural expansion at the N-1-position the yields moderate lipophilic p-(2-fluoroethoxy)benzyl variant 2 (log D=2.2), without loss of caspase binding potency (IC(50, caspase)-3 (2)=36.4 nM).

Results: Subsequent automated radiosynthesis of the corresponding (18)F-labeled target CbR [(18)F]2 was performed by direct (18)F-labeling of tosylate precursor 4.

Conclusions: As shown by biodistribution studies and small animal positron emission tomography a nonpeptidyl 5-pyrrolidinylsulfonyl isatin-type caspase inhibitor (S)-1-(4-(2-[(18)F]Fluoroetho-xy)benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin [(18)F]2 with rapid blood clearance characteristics could potentially detect apoptosis in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspases / metabolism*
  • Isatin / analogs & derivatives*
  • Isatin / chemistry
  • Isatin / pharmacokinetics
  • Isotope Labeling / methods
  • Mice
  • Mice, Nude
  • Positron-Emission Tomography / methods*
  • Pyrrolidines / chemistry*
  • Pyrrolidines / pharmacokinetics*
  • Radiopharmaceuticals / chemical synthesis


  • 1-(4-(2-fluoroethoxy)benzyl)-5-(1-(2-methoxymethylpyrrolidinyl)sulfonyl)isatin
  • Pyrrolidines
  • Radiopharmaceuticals
  • Isatin
  • Caspases