RT Journal Article
SR Electronic
T1 <strong> </strong>PET imaging of [<sup>11</sup>C](R)(-)NR2B-Me, a novel radioligand for the NR2B subunit of the NMDA receptor, in rhesus macaques<strong> </strong>
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 115
OP 115
VO 60
IS supplement 1
A1 Dick, Rachel
A1 Cai, Lisheng
A1 Yan, Xuefeng
A1 Liow, Jeih-San
A1 Morse, Cheryl
A1 Zoghbi, Sami
A1 Frankland, Michael
A1 Gladding, Robert
A1 Pike, Victor
A1 Innis, Robert
YR 2019
UL http://jnm.snmjournals.org/content/60/supplement_1/115.abstract
AB 115Objectives: The NR2B subunit of the N-methyl-D-aspartate (NMDA) receptor is a potential therapeutic target in major depressive disorder, chronic pain, and other nervous system diseases. NR2B antagonists are thought to reduce glutamatergic signaling with fewer side effects than ion channel binding agents. However, previous attempts to develop NR2B radioligands have yielded compounds with high nonspecific binding, including possible binding to the sigma-1 receptor, high test-retest variability, and rapid metabolism. We recently developed a novel PET radioligand, [11C](R)(-)NR2B-Me, for imaging NR2B. Initial rodent studies have demonstrated a favorable pharmacokinetic profile, including extensive brain penetration, high specific binding, and low radiometabolism. In this study, we performed a kinetic evaluation of [11C](R)(-)NR2B-Me in rhesus macaques. Methods: 2 anaesthetized male monkeys underwent 4 dynamic PET scans at baseline and 3 scans after administration of one of three blockers: the cold parent compound; Co 101244, an NR2B antagonist (0.25 mg/kg); or FTC146, a sigma-1 antagonist (0.25 mg/kg). All imaging was conducted on a microPET Focus 220 scanner. Arterial blood samples were collected throughout the scan for the metabolite-corrected input function. Images were co-registered to an MRI template and a set of predefined volumes of interest were applied to generate regional brain time activity curves. Distribution volume (VT) was calculated using a two-tissue compartment model using PMOD software (v3.9). Blocking effect and non-displaceable binding potential (BPND) were determined via Lassen plot and normalized by the free plasma concentration (fP). Results: [11C](R)(-)NR2B-Me readily entered the brain, with good distribution across all regions (average baseline whole brain VT = 29.1). The amygdala and hippocampus showed the highest uptake, reflecting regional differences in NR2B distribution. Co 101244 produced a blocking effect of 96%, indicating that [11C](R)(-)NR2B-Me has high specific binding (non-displaceable distribution volume (VND) = 12.42, BPND = 1.6). A similar blocking effect of 93% was obtained after administration of the cold parent compound (VND = 13.65, BPND = 1.3). FTC146 produced a minimal blocking effect, which demonstrates that the radioligand likely has low affinity for sigma-1 receptors and therefore reduced off-target binding. [11C](R)(-)NR2B-Me showed strong time stability 80 minutes post-injection and slow washout in the baseline condition. Conclusions: Taken together, the high [11C](R)(-)NR2B-Me brain uptake, near-complete blockade by NR2B antagonists, and good time stability indicate that this radioligand is suitable for imaging NR2B distribution in the brain. Human NR2B studies are planned.