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

Abstract

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 (BP(ND) ) 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 (K(d)/f(ND) ~0.23-0.56 nM) was 25- to 48-fold higher than that for the D2R (K(d)/f(ND) ~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.

Elevation of Dopamine Induced by Cigarette Smoking: Novel Insights from a [11C]-(+)-PHNO PET Study in Humans

“…The injected mass of the radiotracer in our study slightly exceed the the mass limit suggested by Gallezot et al (2012), potentially leading to underestimation of dopamine occupancy in both conditions (Shotbolt et al, 2012). The injected mass, however, did not differ between the groups and did not correlate with [ 11 C]-( þ )-PHNO BP ND.…”

Dopamine Response to Psychosocial Stress in Chronic Cannabis Users: A PET Study With [11C]-(+)-PHNO

“…Fourth, baseline estimates of D 2 and D 3 binding were not 'true' baseline measures, as subjects were performing the cognitive (non-stressful) version of the MIST. Fifth, it has recently been suggested that [ 11 C]-( þ )-PHNO may not be at tracer dose in the D 3 -rich regions, which would hinder its accurate quantification (Gallezot et al, 2012;Rabiner and Laruelle, 2010). However, our significant findings were relatively specific to D 2 regions, and scan sessions (SMCT and MIST) were carried out on separate days, at least 5 days apart (except for one subject who could not come on two occasions).…”

Elevated Dopamine D2/3 Receptor Availability in Obese Individuals: A PET Imaging Study with [11C](+)PHNO

“…[ 11 C](+)PHNO was prepared as previously reported (Gallezot et al, 2012). All PET scans were performed with the high-resolution research tomograph (Siemens/CTI, Knoxville, TN, USA), which acquired 207 slices separated by 1.2 mm with a reconstructed image resolution of~3 mm.…”