Design, synthesis and structure–activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents

To continue our efforts toward the development of 99mTc PiB analogs, we have synthesized 24 neutral and lipophilic Re (as a surrogate of 99mTc) 2-arylbenzothiazoles, and explored their structure–activity relationship for binding to Aβ1–40 fibrils. These Re complexes were designed and synthesized via the integrated approach, so their 99mTc analogs would have a greater chance of crossing the blood–brain barrier. While the lipophilicities (log PC18 = 1.59–3.53) of these Re 2-arylbenzothiazoles were all within suitable range, their binding affinities (Ki = 30–617 nM) to Aβ1–40 fibrils varied widely depending on the selection and integration of the tetradentate chelator into the 2-phenylbenzothiazole pharmacophore. For potential clinical applications, further refinement to obtain Re 2-arylbenzothiazoles with better binding affinities (<10 nM) will likely be needed. The integrated approach reported here to generate compact, neutral and lipophilic Re 2-arylbenzothiazoles could be applied to other potent pharmacophores as well to convert other current Aβ PET tracers to their 99mTc analogs for more widespread application via the use of SPECT scanners.

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