Structure−Selectivity Investigations of D₂-Like Receptor Ligands by CoMFA and CoMSIA Guiding the Discovery of D₃Selective PET Radioligands

Abstract

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.

18F‐Labeled FAUC 346 and BP 897 Derivatives as Subtype‐Selective Potential PET Radioligands for the Dopamine D3 Receptor

“…CoMFA and CoMSIA: Taking advantage of our recently described 3D-QSAR models, [31,32] the prediction of D3 selectivities over both congeners D2 and D4 was a crucial part of our strategy. Based on the affinity differences of a training set of 79 ligands, the putative selectivities of the test compounds 4 a-d were calculated.…”

“…The predicted selectivities of the test compounds 4 a-d suggested a subtype-selective profile that is further improved or at least comparable with that of previously investigated fluoro-substituted aryl carboxamides. [30,32] According to these encouraging data, the synthesis of the calculated ligands was envisioned.…”

“…[30] As an extension of this work, we successfully generated CoMFA and CoMSIA models, allowing a precise prediction of D3 affinity and selectivity over both congeners D2 Long and D4 and thus facilitating the development of D3 PET ligands. [31,32] The aim of the present study has been the development of fluorine-labeled PET ligands using FAUC 346 (2 a) as lead compound when the methoxy function should be displaced by a fluoroethoxy bioisostere. …”

A Series of 18F‐Labelled Pyridinylphenyl Amides as Subtype‐Selective Radioligands for the Dopamine D3 Receptor

“…Based on our work on SAR studies guiding the development of D3-selective lead compounds, [3,34,35] we recently reported . [35] In the present work we extended this series of compounds and evaluated the D3 binding specificity of their 18 F-labelled versions in vivo.…”

“…[35] In the present work we extended this series of compounds and evaluated the D3 binding specificity of their 18 F-labelled versions in vivo. We describe the influence of structural changes on a focused library of fluorinated pyridinylbenzamides that were predicted for adequate D3 selectivities and affinities by using CoMFA and CoMSIA methods.…”