title: Novel fluorine-18 labeled 5-(1-pyrrolidinylsulfonyl)-7-azaisatin derivatives as potential PET tracers for in vivo imaging of activated caspases in apoptosis.
abstract: The programmed type I cell death, defined as apoptosis, is induced by complex regulated signaling pathways that trigger the intracellular activation of executioner caspases-3, -6 and -7. Once activated, these enzymes initiate cellular death through cleavage of proteins which are responsible for DNA repair, signaling and cell maintenance. Several radiofluorinated inhibitors of caspases-3 and -7, comprising a moderate lipophilic 5-(1-pyrrolidinylsulfonyl)isatin lead structure, are currently being investigated for imaging apoptosis in vivo by us and others. The purpose of this study was to increase the intrinsic hydrophilicity of the aforementioned lead structure to alter the pharmacokinetic behavior of the resulting caspase-3 and -7 targeted radiotracer. Therefore, fluorinated and non-fluorinated derivatives of 5-(1-pyrrolidinylsulfonyl)-7-azaisatin were synthesized and tested for their inhibitory properties against recombinant caspases-3 and -7. Fluorine-18 has been introduced by copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) of an alkyne precursor with 2-[(18)F]fluoroethylazide. Using dynamic micro-PET biodistribution studies in vivo the kinetic behavior of one promising PET-compatible 5-pyrrolidinylsulfonyl 7-azaisatin derivative has been compared to a previously described isatin based radiotracer.
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany. Electronic address: cwaldmann@mednet.ucla.edu.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Waldmann
authors.affiliation: European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 11, D-48149 Münster, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Hermann
authors.affiliation: European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 11, D-48149 Münster, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Faust
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Riemann
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany.
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany; European Institute for Molecular Imaging (EIMI), University of Münster, Waldeyerstraße 11, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.affiliation: Organic Chemistry Institute, University of Münster, Corrensstrasse 40, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), University of Münster, Waldeyerstraße 15, D-48149 Münster, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Haufe
authors.affiliation: Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry; D020169:Caspases / Q000378:metabolism*; D057930:Click Chemistry; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007510:Isatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D007553:Isotope Labeling; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D007510:Isatin; D020169:Caspases
keywords: (18)F-radiolabeling; 7-Azaisatin; Apoptosis; Caspase inhibitor; Click-chemistry; Positron emission tomography (PET)