Structure-selectivity investigations of D2-like receptor ligands by CoMFA and CoMSIA guiding the discovery of D3 selective PET radioligands.
Structure-selectivity investigations of D2-like receptor ligands by CoMFA and CoMSIA guiding the discovery of D3 selective PET radioligands.
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DOI：
10.1021/jm0611152
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发表时间：
2007-01
影响因子：
7.3
通讯作者：
I. Salama;C. Hocke;W. Utz;O. Prante;F. Boeckler;H. Hübner;T. Kuwert;P. Gmeiner
中科院分区：
文献类型：
--
作者：
I. Salama;C. Hocke;W. Utz;O. Prante;F. Boeckler;H. Hübner;T. Kuwert;P. Gmeiner
由于缺乏生物可利用的亚型选择性示踪配体，利用正电子发射断层扫描（PET）阐明D3受体的生理作用及其在大脑中的分布受到阻碍。为了开发合适的D3放射配体，我们设计了一个综合程序，包括通过比较分子分析来阐明决定D3对同系物D2和D4选择性的结构特征。因此，我们基于一系列代表广泛选择性的79个配体的亲和差异成功地生成了CoMFA和CoMSIA模型。这些模型得到了高度显著的交叉验证(q2cv(D3/D2) = 0.86；q2cv(D3/D4) = 0.92)和16配体测试集的良好预测（r2pred = 0.79-0.93）。利用这些信息，合成和受体结合研究将我们引向了含氟先导化合物78和79，它们具有亚纳摩尔的D3亲和性，比D2和D4具有相当大的选择性，随后又指向了亚型选择性PET示踪剂[18F]78和[18F]79。
Elucidation of the physiological role of the D3 receptor and its distribution in the brain using positron emission tomography (PET) is hampered by the lack of bioavailable subtype selective tracer ligands. To develop appropriate D3 radioligands, we designed an integrative procedure involving the elucidation of structural features determining D3 selectivity over both congeners D2 and D4 by comparative molecular analysis. Thus, we have successfully generated CoMFA and CoMSIA models based on the affinitiy differences of a series of 79 ligands representing a broad range of selectivities. These models yielded highly significant cross-validations (q2cv(D3/D2) = 0.86; q2cv(D3/D4) = 0.92) and excellent predictions of a 16-ligand test set (r2pred = 0.79-0.93). Exploiting this information, synthesis and receptor binding studies directed us to the fluorinated lead compounds 78 and 79, featuring subnanomolar D3 affinities and considerable selectivities over D2 and D4 and, subsequently, to the subtype selective PET tracers [18F]78 and [18F]79.