Structure-Selectivity Investigations of D2-Like Receptor Ligands by CoMFA and CoMSIA Guiding the Discovery of D3 Selective PET Radioligands

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• 作者：Ismail Salama ; Carsten Hocke ; Wolfgang Utz ; Olaf Prante ; Frank Boeckler ; Harald H&uuml ; bner ; Torsten Kuwert ; Peter Gmeiner
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：February 8, 2007
• 年：2007
• 卷：50
• 期：3
• 页码：489 - 500
• 全文大小：541K
• 年卷期：v.50,no.3(February 8, 2007)
• ISSN：1520-4804

文摘

Elucidation of the physiological role of the D₃ receptor and its distribution in the brain using positron emissiontomography (PET) is hampered by the lack of bioavailable subtype selective tracer ligands. To developappropriate D₃ radioligands, we designed an integrative procedure involving the elucidation of structuralfeatures 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 seriesof 79 ligands representing a broad range of selectivities. These models yielded highly significant cross-validations (q²_cv(D₃/D₂) = 0.86; q²_cv(D₃/D₄) = 0.92) and excellent predictions of a 16-ligand test set (r²_pred= 0.79-0.93). Exploiting this information, synthesis and receptor binding studies directed us to the fluorinatedlead compounds 78 and 79, featuring subnanomolar D₃ affinities and considerable selectivities over D₂ andD₄ and, subsequently, to the subtype selective PET tracers [¹⁸F]78 and [¹⁸F]79.