Synthesis and β-amyloid binding properties of rhenium 2-phenylbenzothiazoles

As a first step toward the development of 99mTc PiB analogs, we have synthesized six neutral Re 2-phenylbenzothiazoles via pendant or integrated approach. These Re compounds bind to Aβ1–40 fibrils with fairly good affinities (Ki = 10.0–88.6 nM) and have moderate lipophilicities (log PC18 = 1.21–3.26). The Re compounds prepared via the integrated approach are smaller in size, and therefore their corresponding 99mTc 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 (<10 nM) 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 99mTc analogs that could hold promise for extending the use of Aβ imaging in living human brain to many more clinical settings because they could be used with SPECT.

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