title: Synthesis, 18F-radiolabeling, and in vivo biodistribution studies of N-fluorohydroxybutyl isatin sulfonamides using positron emission tomography.
abstract: The effector caspases-3 and -7 play a central role in programmed type I cell death (apoptosis). Molecular imaging using positron emission tomography (PET) by tracking the activity of executing caspases might allow the detection of the early onset as well as therapy monitoring of various diseases induced by dysregulated apoptosis. Herein, four new fluorinated diastereo- and enantiopure isatin sulfonamide-based potent and selective caspase-3 and -7 inhibitors were prepared by cyclic sulfate ring-opening with fluoride. All fluorohydrins exhibited excellent in vitro affinities (up to IC50 = 11.8 and 0.951 nM for caspase-3 and -7, respectively), which makes them appropriate PET radiotracer candidates. Therefore, N-(4-[(18)F]fluoro-3(R)-hydroxybutyl)- and N-(3(S)-[(18)F]fluoro-4-hydroxybutyl)-5-[1-(2(S)-(methoxymethyl)pyrrolidinyl)sulfonyl]isatin were synthesized in 140 min with 24% and 10% overall radiochemical yields and specific activities of 10-127 GBq/μmol using [(18)F]fluoride in the presence of Kryptofix and subsequent acidic hydrolysis. In vivo biodistribution studies in wild-type mice using PET/computed tomography imaging proved fast clearance of the tracer after tail vein injection.
authors: Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, D-48149 Münster, Germany.
authors: Panupun
authors: P
authors: Limpachayaporn
authors: Stefan
authors: S
authors: Wagner
authors: Klaus
authors: K
authors: Kopka
authors: Sven
authors: S
authors: Hermann
authors: Michael
authors: M
authors: Schäfers
authors: Günter
authors: G
authors: Haufe
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000737:chemistry; D053179:Caspase 7 / Q000737:chemistry; D061945:Caspase Inhibitors / Q000737:chemistry; D005462:Fluorine Radioisotopes; D006801:Humans; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051379:Mice; D008958:Models, Molecular; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed
chemical_list: D061945:Caspase Inhibitors; D005462:Fluorine Radioisotopes; C582918:N-(3-fluoro-4-hydroxybutyl)-5-(1-(2-(methoxymethyl)pyrrolidinyl)sulfonyl)isatin; C582919:N-(4-fluoro-3-hydroxybutyl)-5-(1-(2-(methoxymethyl)pyrrolidinyl)sulfonyl)isatin; D019275:Radiopharmaceuticals; D013449:Sulfonamides; D007510:Isatin; D053148:Caspase 3; D053179:Caspase 7