Year: 2010
Type: article
Abstract: Dopamine D3 receptors (D3Rs) may afford the ability to treat a wide variety of neuropsychiatric disorders (Graff-Guerrero et al.2009b). 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.2009b; Rabiner et al.2009). Graff-Guerrero et al. (2009b) 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. (2009b) paper. In their commentary they assert that ABT-925 is unsuitable as a selective antagonist alongside [11C](+)-PHNO to image D3Rs due to its limited selectivity for D3Rs in vivo. We maintain that the experiment with ABT-925 demonstrates the usefulness of [11C](+)-PHNO to examine in vivo the relationship between human D3R binding and plasma exposures with D3R antagonists. First, Rabiner & Laruelle (2010) note that the relative density of D2Rs in most brain regions is significantly higher than that of D3Rs and this affects the utility of [11C](+)-PHNO to determine D3R occupancy status for ABT-925. While it is true that in most areas D2R density is greater than D3R density, there is compelling evidence that there are human brain regions with sufficient D3R exclusivity to allow determination of D3R occupancy using [11C](+)-PHNO. Moreover, recent human PET studies in schizophrenia using [11C](+)-PHNO demonstrated that chronic antipsychotic treatment with olanzapine, clozapine or risperidone, produced high levels of receptor occupancy in D2Rs but not D3R-rich regions such as globus pallidus, while the addition of pramipexole displaced [11C](+)-PHNO in the globus pallidus (Graff-Guerrero et al.2009a). Further, Rabiner and colleagues have demonstrated in non-human primates that some midbrain and forebrain regions express D3R exclusively, whilst other regions exhibit a mixed D2R/D3R population (Graff-Guerrero et al.2009b; Rabiner et al.2009). It is those D3-selective regions that unequivocally demonstrate D3R target engagement with ABT-925, which was the over-riding goal of our study. Second, Rabiner & Laruelle (2010) note that [11C](+)-PHNO has only ∼20-fold selectivity for D3R over D2R in vivo. Whilst we agree that [11C](+)-PHNO is not a D3-selective tracer, we respectfully note that there is no precise determination of the selectivity of [11C](+)-PHNO, as recently noted in Rabiner et al. (2009). Indeed, previous studies of [11C](+)-PHNO affinity at D2 and D3 receptors have demonstrated between a 30- to 50-fold selectivity in vitro (Freedman et al.1994; Rabiner et al.2009). Accordingly, BP-897, a D3R partial agonist with a 70-fold selectivity in vitro, produces 57% blockade of PHNO binding in D3R-rich regions and 29% blockade in mixed D2R/D3R regions (Narendran et al.2006). The authors concluded that the receptor occupancies of BP-897 were sufficient to demonstrate that [11C](+)-PHNO was a D3R-preferring agonist. The evolution of our understanding regarding the true utility of [11C](+)-PHNO to determine target engagement prior to 2009 was challenging. However, advances were driven by several studies that demonstrated [11C](+)-PHNO was unique from other D2R/D3R PET ligands, as the highest regional binding was observed in the globus pallidus (Ginovart et al.2006; Narendran et al.2009; Rabiner et al.2009; Willeit et al.2008). Using the D2R antagonist SV-156 (20-fold selective over D3) and the D3R partial agonist BP-187 (70-fold selective over D2), Laruelle and colleagues demonstrated the first in-vivo pharmacological evidence that there were D3R-preferring regions such as the globus pallidus (Narendran et al.2006). However, the fractions of [11C](+)-PHNO binding attributable to D3Rs in these regions were unknown. In an elegant study employing the D3R antagonist SB277011 (100-fold selective over D2in vitro), in non-human primates as well as D2R and D3R knockout mice, the fraction of the [11C](+)-PHNO signal that accounted for D3 and D2 receptors was determined. Those data, using quantitative autoradiography and in-vivo PET, demonstrate that binding in the midbrain is entirely attributable to D3Rs (Rabiner et al.2009). A consistent pattern of effects has been demonstrated across all these validation studies; D3R selective regions show the most receptor occupancy for D3R antagonists, and mixed D2R/D3R regions show lower occupancies (Graff-Guerrero et al.2008, 2009a, b; Narendran et al.2006; Rabiner et al.2009). For example, using SB-277011 Rabiner and colleagues observed greatest binding in the substantial nigra, thalamus and globus pallidus with low receptor binding in the caudate and putamen. The significant, although numerically smaller, receptor occupancy for ABT-925 in the caudate and putamen compared to the substantia nigra and globus pallidus are consistent with a blockade of [11C](+)-PHNO by ABT-925 at D3Rs vs. D2Rs. In conclusion, by utilizing regions of interest that are enriched for D3Rs (Rabiner et al.2009), Graff-Guerrero and colleagues (2009b) have successfully demonstrated that ABT-925 can occupy up to 74% of D3Rs in human CNS. Moreover, the absence of D2R antagonist-associated adverse events with ABT-925 demonstrates that there is a significant and meaningful separation from D2R occupancy in humans. Such data support the conclusion that D3R target engagement can be assessed for the D3R-selective antagonist, ABT-925, in humans using [11C](+)-PHNO. None. All authors are employees of Abbott Laboratories.
Authors: Mark Day, Earle Bain, Gerard Marek, Mario Saltarelli, Gerard B. Fox
Institution: Abbott (United States)
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2150128170