Design, synthesis and structure-activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents.
Design, synthesis and structure-activity relationship of rhenium 2-arylbenzothiazoles as β-amyloid plaque binding agents.
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DOI：
10.1016/j.bmcl.2013.01.068
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发表时间：
2013-03-15
影响因子：
2.7
通讯作者：
Lin, Kuo-Shyan
中科院分区：
文献类型：
--
作者：
Pan, Jinhe;Mason, Neale S.;Debnath, Manik L.;Mathis, Chester A.;Klunk, William E.;Lin, Kuo-Shyan
为了继续开发99 mTc PiB类似物，我们合成了24个中性亲脂性Re（99 mTc的替代物）2-芳基苯并噻唑类化合物，并探讨了它们与Aβ1- 40纤维结合的构效关系。这些Re配合物是通过集成方法设计和合成的，因此它们的99 mTc类似物将有更大的机会穿过血脑屏障。虽然这些Re 2-芳基苯并噻唑的亲脂性（logPC 18 = 1.59-3.53）都在合适的范围内，但它们与Aβ1-40原纤维的结合亲和力（Ki= 30-617 nM）变化很大，这取决于四齿螯合剂的选择和整合到2-苯基苯并噻唑药效团中。对于潜在的临床应用，可能需要进一步改进以获得具有更好结合亲和力（< 10 nM）的Re 2-芳基苯并噻唑。本文报道的生成致密、中性和亲脂性Re 2-芳基苯并噻唑的综合方法可应用于其他有效的药效团，也可通过使用SPECT扫描仪将其他当前Aβ PET示踪剂转化为其99 mTc类似物，以获得更广泛的应用。
To continue our efforts toward the development of 99mTc PiB analogs, we have synthesized twenty-four neutral and lipophilic Re (as a surrogate of 99mTc) 2-arylbenzothiazoles, and explored their structure-activity relationship for binding to Aβ1–40fibrils. 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 (logPC18= 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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