[18F]- and [11C]-labeled N-benzyl-isatin sulfonamide analogues as PET tracers for apoptosis: synthesis, radiolabeling mechanism, and in vivo imaging study of apoptosis in Fas-treated mice using [11C]WC-98.
The radiolabeled isatin sulfonamide caspase-3 inhibitor, [18F] 2 (WC-II-89), is a potential PET radiotracer for noninvasive imaging of apoptosis. The radiolabeling mechanism was studied by 13C NMR, ESI/MS, and computational calculations. It was found that the high electrophilicity of the C3 carbonyl group in the isatin ring, which served as a trap for [18F]fluoride, was responsible for the failure of the radiolabeling via nucleophilic substitution of the mesylate group in 7a by [18F]fluoride. Once treated with a strong base, 7a opened the isatin ring completely to form an isatinate intermediate 16, which lost the ability to trap [18F]fluoride, thereby allowing the displacement of the mesylate group to afford the 18F-labeled isatinate 17. [18F] 17 can be converted to isatin [18F] 2 efficiently under acidic conditions. The ring-opening and re-closure of the isatin ring under basic and acidic conditions were confirmed by reversed phase HPLC analysis, ESI/MS and 13C NMR studies. Computational studies of model compounds also support the above proposed mechanism. Similarly, the ring-opening and re-closure method was used successfully in the synthesis of the 11C labeled isatin sulfonamide analogue [11C] 4 (WC-98). A microPET imaging study using [11C] 4 in the Fas liver apoptosis model demonstrated retained activity in the target organ (liver) of the treated mice. Increased caspase-3 activation in the liver was verified by the fluorometric caspase-3 enzyme assay. Therefore, this study provides a useful method for radio-synthesis of isatin derivative radiotracers for PET and SPECT studies, and [11C] 4 is a potential PET radiotracer for noninvasive imaging of apoptosis.
Zhou
Dong
D
Division of Radiological Sciences, Washington University School of Medicine, Campus Box 8225 510 S. Kingshighway Blvd. St. Louis, Missouri 63110, USA.
Chu
Wenhua
W
Chen
Delphine L
DL
Wang
Qi
Q
Reichert
David E
DE
Rothfuss
Justin
J
D'Avignon
Andre
A
Welch
Michael J
MJ
Mach
Robert H
RH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis / Q000187:drug effects*; D002250:Carbon Radioisotopes; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D005260:Female; D005462:Fluorine Radioisotopes; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007510:Isatin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D007553:Isotope Labeling; D008099:Liver / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008807:Mice, Inbred BALB C; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019014:fas Receptor / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D007211:Indoles; D019275:Radiopharmaceuticals; D013449:Sulfonamides; C540207:WC-II-89; C411023:anti-Fas monoclonal antibody; D019014:fas Receptor; D007510:Isatin