title: Synthesis of 7-halogenated isatin sulfonamides: nonradioactive counterparts of caspase-3/-7 inhibitor-based potential radiopharmaceuticals for molecular imaging of apoptosis.
abstract: N-Alkylated (S)-7-halogen-5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatins were developed as a new group of nonradioactive reference compounds for future radiotracers. Inhibitor potency studies of these compounds suggest that the binding pockets readily accommodate both the 7-halogen substituents and aliphatic side chains (methyl to n-butyl) as well as some ω-fluorinated analogues (3-fluoropropyl and 4-fluorobutyl) at the isatin nitrogen. Indeed, compared to the halogen free parent compounds, some 7-halogenated derivatives exhibited slightly improved inhibitory potencies with IC50 values up to 2.6 nM (caspase-3) and 3.3 nM (caspase-7), respectively. Moreover, the 7-position of isatin, a potential cytochrome P450 hydroxylation site, was substituted by I, Br, Cl, and F to potentially enhance the metabolic stability of isatin sulfonamides. As an example, the radiotracer [(18)F]39 that was produced by (19)F/(18)F isotope exchange was shown to be stable in human blood serum after incubation at 37 °C for at least 90 min.
authors.affiliation: Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster , Corrensstraße 40, D-48149 Münster, Germany.
authors.forename: Panupun
authors.initials: P
authors.lastname: Limpachayaporn
authors.forename: Stefan
authors.initials: S
authors.lastname: Wagner
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.forename: Otmar
authors.initials: O
authors.lastname: Schober
authors.forename: Michael
authors.initials: M
authors.lastname: Schäfers
authors.forename: Günter
authors.initials: G
authors.lastname: Haufe
mesh_terms: D017209:Apoptosis; D053148:Caspase 3 / Q000737:chemistry; D053179:Caspase 7 / Q000737:chemistry; D061945:Caspase Inhibitors / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006219:Halogens / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007510:Isatin / Q000138:chemical synthesis* / Q000737:chemistry; D057054:Molecular Imaging / Q000295:instrumentation / Q000379:methods; D019275:Radiopharmaceuticals / Q000737:chemistry*; D044967:Serum / Q000187:drug effects; D012997:Solvents / Q000737:chemistry; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry; D013696:Temperature; D013997:Time Factors
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D006219:Halogens; D019275:Radiopharmaceuticals; D012997:Solvents; D013449:Sulfonamides; D007510:Isatin; D003577:Cytochrome P-450 Enzyme System; D053148:Caspase 3; D053179:Caspase 7