Bioorganic & Medicinal Chemistry Letters 2009-04-15

Synthesis and beta-amyloid binding properties of rhenium 2-phenylbenzothiazoles.

Kuo-Shyan Lin, Manik L Debnath, Chester A Mathis, William E Klunk

Index: Bioorg. Med. Chem. Lett. 19(8) , 2258-62, (2009)

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Abstract

As a first step toward the development of (99m)Tc PiB analogs, we have synthesized six neutral Re 2-phenylbenzothiazoles via pendant or integrated approach. These Re compounds bind to Abeta(1-40) fibrils with fairly good affinities (K(i)=10.0-88.6nM) and have moderate lipophilicities (logP(C18)=1.21-3.26). The Re compounds prepared via the integrated approach are smaller in size, and therefore their corresponding (99m)Tc analogs would have a greater chance of crossing the blood-brain barrier well. For potential clinical applications, further optimization on the structure-activity relationship to obtain Re 2-phenylbenzothiazoles with higher binding affinities (<10nM) might be needed. The integrated approach reported here to obtain neutral, compact and lipophilic Re 2-phenylbenzothiazoles could to be applied to other high affinity pharmacophores as well as to generate (99m)Tc analogs that could hold promise for extending the use of Abeta imaging in living human brain to many more clinical settings because they could be used with SPECT.