Affinity and selectivity of [11C]-(+)-PHNO for the D3 and D2 receptors in the rhesus monkey brain in vivo

• Published in: Synapse (New York, N.Y.) N.Y.), 2012-06, Vol.66 (6), p.489-500
• Main Authors: Gallezot, Jean-Dominique, Beaver, John D., Gunn, Roger N., Nabulsi, Nabeel, Weinzimmer, David, Singhal, Tarun, Slifstein, Mark, Fowles, Krista, Ding, Yu-Shin, Huang, Yiyun, Laruelle, Marc, Carson, Richard E., Rabiner, Eugenii A.
• Format: Article
• Language: English
• Subjects: Animals; Benzoxazines - chemistry; Benzoxazines - metabolism; Binding, Competitive; brain; Brain - diagnostic imaging; Brain - metabolism; Carbon Radioisotopes - chemistry; D2 receptor; D3 receptor; Dopamine Agonists - metabolism; Female; in vivo; Macaca mulatta - metabolism; Naphthols - chemistry; Naphthols - metabolism; Oxazines - metabolism; PET; Positron-Emission Tomography; primate; Receptors, Dopamine D2 - metabolism; Receptors, Dopamine D3 - metabolism; Substrate Specificity
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.21535

Although [11C]‐(+)‐PHNO has enabled quantification of the dopamine‐D3 receptor (D3R) in the human brain in vivo, its selectivity for the D3R is not sufficiently high to allow us to disregard its binding to the dopamine‐D2 receptor (D2R). We quantified the affinity of [11C]‐(+)‐PHNO for the D2R and D3R in the living primate brain. Two rhesus monkeys were examined on four occasions each, with [11C]‐(+)‐PHNO administered in a bolus + infusion paradigm. Varying doses of unlabeled (+)‐PHNO were coadministered on each occasion (total doses ranging from 0.09 to 5.61 μg kg−1). The regional binding potential (BPND) and the corresponding doses of injected (+)‐PHNO were used as inputs in a model that quantified the affinity of (+)‐PHNO for the D2R and D3R, as well as the regional fractions of the [11C]‐(+)‐PHNO signal attributable to D3R binding. (+)‐PHNO in vivo affinity for the D3R (Kd/fND ∼ 0.23–0.56 nM) was 25‐ to 48‐fold higher than that for the D2R (Kd/fND ∼ 11–14 nM). The tracer limits for (+)‐PHNO (dose associated with D3R occupancy ∼ 10%) were estimated at ∼0.02–0.04 μg kg−1 injected mass for anesthetized primate and at 0.01–0.02 μg kg−1 for awake human positron emission tomography (PET) studies. Our data enabled a rational design and interpretation of future PET studies with [11C]‐(+)‐PHNO. Synapse, 2012. © 2011 Wiley Periodicals, Inc.