title: 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.
abstract: OBJECTIVE
  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.
authors: Department of Nuclear Medicine, University Hospital Muenster, Muenster, Germany.
authors: A
authors: A
authors: Faust
authors: S
authors: S
authors: Wagner
authors: M P
authors: MP
authors: Law
authors: S
authors: S
authors: Hermann
authors: U
authors: U
authors: Schnöckel
authors: P
authors: P
authors: Keul
authors: O
authors: O
authors: Schober
authors: M
authors: M
authors: Schäfers
authors: B
authors: B
authors: Levkau
authors: K
authors: K
authors: Kopka
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D007510:Isatin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods*; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis
chemical_list: C516218:1-(4-(2-fluoroethoxy)benzyl)-5-(1-(2-methoxymethylpyrrolidinyl)sulfonyl)isatin; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D007510:Isatin; D020169:Caspases