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D3 receptor target engagement in humans with ABT-925 using [11C](+)-PHNO PET.

Dopamine D3 receptors (D3Rs) may afford the ability to treat a wide variety of neuropsychiatric disorders (Graff-Guerrero et al. 2009 b ). Until recently, there was no non-invasive way to determine the physical interaction of antagonists with D3Rs in animals and humans. In part, this was driven by the absence of a D3R-selective PET tracer and the co-localization of D2 and D3 receptors in the CNS. Further, in most brain regions, D2R density is higher than D3R density. Recently, the identification of midbrain regions that are selective for D3R have been revealed using [11C](+)-PHNO, affording a method to determine the level of target engagement of D3R antagonists (Graff-Guerrero et al. 2009 b ; Rabiner et al. 2009).

Graff-Guerrero et al. (2009 b ) have demonstrated that the D3R antagonist, ABT-925, can block up to 74% of D3Rs in humans at doses tested. Moreover, no D2R antagonist-associated adverse events were observed with ABT-925, indicating a significant and meaningful separation from D2R occupancy in humans. Recently, Rabiner & Laruelle (2010) have provided a commentary on the Graff-Guerrero et al. (2009 b ) paper. In their commentary they assert that ABT-925 is unsuitable as a selective antagonist alongside …