In Vitro and In Vivo Evaluation of N‐{2‐[4‐(3‐Cyanopyridin‐2‐yl)piperazin‐1‐yl]ethyl}‐3‐[¹¹C]methoxybenz­amide, a Positron Emission Tomography (PET) Radioligand for Dopamine D₄ Receptors, in Rodents

Abstract

The D4 dopamine receptor belongs to the D2 -like family of dopamine receptors, and its exact regional distribution in the central nervous system is still a matter of considerable debate. The availability of a selective radioligand for the D4 receptor with suitable properties for positron emission tomography (PET) would help resolve issues of D4 receptor localization in the brain, and the presumed diurnal change of expressed protein in the eye and pineal gland. We report here on in vitro and in vivo characteristics of the high-affinity D4 receptor-selective ligand N-{2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl}-3-[(11) C]methoxybenzamide ([(11) C]2) in rat. The results provide new insights on the in vitro properties that a brain PET dopamine D4 radioligand should possess in order to have improved in vivo utility in rodents.

Expression of a Novel D4 Dopamine Receptor in the Lamprey Brain. Evolutionary Considerations about Dopamine Receptors

“…Moreover, important discrepancies exist among these studies so that a detailed expression pattern of the D4 receptor is not clear yet, even in mammals. The D4 receptor has attracted interest because of its potential role mediating the effects of some atypical antipsychotics or drug addiction ( Rondou et al, 2010 ; Sampson et al, 2014 ), but historically, it has been difficult to study because of the lack of true selective agonists (see Rondou et al, 2010 ) and studies to identify specific ligands against the D4 receptor are still being carried out nowadays ( Abdelfattah et al, 2013 ; Kügler et al, 2013 ; Lacivita et al, 2014 ; Leopoldo et al, 2014 ; Sampson et al, 2014 ). In addition, the antibodies developed against the D4 receptor have been shown to be insufficiently selective and sensitive ( Kubikova et al, 2010 ; Rondou et al, 2010 ), and only a few studies have used in situ hybridization to analyze the D4 receptor expression pattern ( Meador-Woodruff et al, 1994 , 1996 , 1997 ; Lidow et al, 1998 ; Callier et al, 2003 ; Noaín et al, 2006 ; Boehmler et al, 2007 ; Zhu et al, 2007 ; Kubikova et al, 2010 ).…”

“…In addition, the antibodies developed against the D4 receptor have been shown to be insufficiently selective and sensitive ( Kubikova et al, 2010 ; Rondou et al, 2010 ), and only a few studies have used in situ hybridization to analyze the D4 receptor expression pattern ( Meador-Woodruff et al, 1994 , 1996 , 1997 ; Lidow et al, 1998 ; Callier et al, 2003 ; Noaín et al, 2006 ; Boehmler et al, 2007 ; Zhu et al, 2007 ; Kubikova et al, 2010 ). Altogether, this makes that the expression pattern of this receptor is still a matter of debate ( Leopoldo et al, 2014 ).…”