C PHNO has been described as
[11C]-(+)-PHNO has been described as a full agonist at both D2 and D3 receptors [54,55]. [11C]-(+)-PHNO was initially developed as a PET radiotracer for imaging the high affinity state of the D2 receptor (i.e., highD2) as a means of measuring synaptic dopamine changes in response to pharmacologic challenge [56,57]. Subsequent studies revealed that there was no difference in the displacement of [11C]-(+)-PHNO and [3H]raclopride by dopamine antagonists and agonists; these data led the investigators to conclude that PHNO was a nonselective D2/D3 ligand, and questioned the existence of the highD2 in vivo [58,59]. PET imaging studies in humans revealed that the regional distribution of [11C]-(+)-PHNO was different from [11C]raclopride . Since [11C]-(+)-PHNO is thought to have a higher D3 affinity than [11C]raclopride, these results were explained by [11C]-(+)-PHNO labeling a higher population of D3 receptors, and subsequently led to the description of [11C]-(+)-PHNO as a D3-preferring radioligand [54,61]. Like [11C]raclopride and [18F]fallypride, [11C]-(+)-PHNO has been used to determine the in vivo receptor occupancy of drugs . Because of the overlap with D2, investigators using [11C]-(+)-PHNO have used independent component analysis to help tease out the D3 signal [63,64]. This approach remains sub-optimal due to co-expression of both D3 and D2 dopamine receptor subtype in the same Arylquin 1 regions .
PET imaging of human uptake of what may be the first D3-selective radiotracer [18F]fluortriopride ([18F]FTP)  are under way, but no results have been published to date and therefore human uptake results of this new radiotracer are too preliminary to be included in this review.
Assessing selectivity of radiotracers between dopamine D2 and D3 receptors As stated above, D2 and D3 receptors have an 80% sequence homology within the seven transmembrane regions that contain the ligand binding regions [2,3,13], which has made it difficult to develop a D3-selective radiotracer. Dopamine D3/D2 selectivity has been defined by MacDonald et al. as the antilogarithm of the difference between D3 and D2 pKi values . This definition of D3/D2 selectivity is equivalent to the ratio of a ligand’s D2 Ki value to its D3 Ki value that has been reported by other groups . While the Macdonald et al. in vitro D3/D2 selectivity metric or equivalent is widely reported when discussing new D3-targeting ligands, this measure may not be optimal for assessing D3/D2 selectivity in vivo due to complications caused by receptor occupancy from endogenous dopamine. This is discussed in greater detail in the following subsections.
Future work and challenges
Conflicts of interest
Acknowledgements Research reported in this publication was supported by the National Institute On Drug Abuse of the National Institutes of Health under Award Numbers K01DA040023, K23DA038726, and R01DA029840. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Introduction The Substantia Nigra pars reticulata (SNr) represents the output station of basal ganglia circuitry and, according to the current model, the activity of its neurons determines motor behavior (Robertson, 1992). Nigral neurons have tonic firing and are controlled by GABAergic and glutamatergic afferents (Zhou and Lee, 2011). GABAergic input is provided by striatal and pallidal afferents, whereas glutamatergic input is mainly provided by the subthalamic nucleus (Parent and Hazrati, 1995). Dopamine released in SNr by dendrites from substantia nigra pars compacta neurons (Geffen et al., 1976) controls GABA and glutamate release through presynaptic receptors. The presynaptic control of glutamate release by dopamine involves D1-like and D2-like receptors. D1-like receptors, probably D5 receptors (D5R) (Svenningsson and Le Moine, 2002), increase glutamate release (Rosales et al., 1997, Ibanez-Sandoval et al., 2006, Cortes et al., 2010). On the other hand, one study (Ibanez-Sandoval et al., 2006) did not define the D2-like subtype involved in glutamate release. Another study (Shen and Johnson, 2012) showed that pharmacologically defined D3 receptors (D3R) modulate inhibitory release of glutamate. The role of D4 receptors (D4R) has not been clearly established (Shen and Johnson, 2012). Apparently, the glutamatergic subthalamo-nigral projection has no D4R, since subthalamic nucleus neurons do not express D4 messenger RNA (mRNA) (Flores et al., 1999, Ramanathan et al., 2008). From these considerations, it can be observed that the relative contribution of dopamine receptor subtypes to the control of total glutamate release, their pharmacological properties, and their possible interactions have not, to our knowledge, been studied. This is important, in that the prevalence of an effect, either stimulatory or inhibitory on release, would determine the amount of glutamate in the SNr, thereby the firing rate of the output neurons and motor activity (Zhou and Lee, 2011). To date, the interaction of D1-like with D2R, D3R, and/or D4R in the control of glutamate release has not been described.