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A Journal on Nuclear Medicine and Molecular Imaging
Affiliated to the and to the International Research Group of Immunoscintigraphy
Indexed/Abstracted in: Current Contents/Clinical Medicine, EMBASE, PubMed/MEDLINE, Science Citation Index (SciSearch), Scopus
Impact Factor 2,413
RADIOPHARMACY AND RADIOPHARMACEUTICALS 2007 UPDATE
Faust A. 1, 2, Wagner S. 1, Law M. P. 1, Hermann S. 1, Schnöckel U. 1, Keul P. 1, 2, Schober O. 1, Schäfers M. 1, 2, Levkau B. 3, Kopka K. 1, 2
1 Department of Nuclear Medicine University Hospital Muenster, Muenster, Germany
2 Interdisciplinary Center of Clinical Research (IZKF) Muenster, Germany
3 Institute of Pathophysiology, Center of Internal Medicine University Hospital Essen, Essen, Germany
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 (Ki, 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 (IC50, caspase-3 (2)=36.4 nM).
Results. Subsequent automated radiosynthesis of the corresponding 18F-labeled target CbR [18F]2 was performed by direct 18F-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-[18F]Fluoroetho-xy)benzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin [18F]2 with rapid blood clearance characteristics could potentially detect apoptosis in vivo.