Affinity and selectivity of [¹¹C]-(+)-PHNO for the D3 and D2 receptors in the rhesus monkey brain in vivo.
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.
PET Center, Department of Diagnostic Radiology, Yale University, New Haven, Connecticut, USA.
Jean-Dominique
JD
Gallezot
John D
JD
Beaver
Roger N
RN
Gunn
Nabeel
N
Nabulsi
David
D
Weinzimmer
Tarun
T
Singhal
Mark
M
Slifstein
Krista
K
Fowles
Yu-Shin
YS
Ding
Yiyun
Y
Huang
Marc
M
Laruelle
Richard E
RE
Carson
Eugenii A
EA
Rabiner
D000818:Animals; D048588:Benzoxazines / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry; D018491:Dopamine Agonists / Q000378:metabolism*; D005260:Female; D008253:Macaca mulatta / Q000378:metabolism; D009284:Naphthols / Q000737:chemistry / Q000378:metabolism*; D010078:Oxazines / Q000378:metabolism*; D049268:Positron-Emission Tomography; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D013379:Substrate Specificity
C574079:4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho(1,2-b)(1,4)oxazin-9-ol; D048588:Benzoxazines; D002250:Carbon Radioisotopes; D018491:Dopamine Agonists; D009284:Naphthols; D010078:Oxazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C042631:naxagolide