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Synthesis of 7‑Halogenated Isatin Sulfonamides: Nonradioactive Counterparts of Caspase-3/‑7 Inhibitor-Based Potential Radiopharmaceuticals for Molecular Imaging of Apoptosis

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journal contribution
posted on 26.11.2014, 00:00 by Panupun Limpachayaporn, Stefan Wagner, Klaus Kopka, Otmar Schober, Michael Schäfers, Günter Haufe
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 [18F]39 that was produced by 19F/18F isotope exchange was shown to be stable in human blood serum after incubation at 37 °C for at least 90 min.