RT Journal Article
SR Electronic
T1 Determination of In Vivo <em>B</em><sub>max</sub> and <em>K</em><sub>d</sub> for <sup>11</sup>C-GR103545, an Agonist PET Tracer for κ-Opioid Receptors: A Study in Nonhuman Primates
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 600
OP 608
DO 10.2967/jnumed.112.112672
VO 54
IS 4
A1 Giampaolo Tomasi
A1 Nabeel Nabulsi
A1 Ming-Qiang Zheng
A1 David Weinzimmer
A1 Jim Ropchan
A1 Laura Blumberg
A1 Clive Brown-Proctor
A1 Yu-Shin Ding
A1 Richard E. Carson
A1 Yiyun Huang
YR 2013
UL http://jnm.snmjournals.org/content/54/4/600.abstract
AB The κ-opioid receptors (KOR) are involved in mood disorders and addictive conditions. In vivo imaging studies of this receptor in humans have not been reported because of the lack of a selective ligand. We used a recently developed selective KOR agonist tracer, 11C-GR103545, and performed a study in rhesus monkeys to estimate the in vivo receptor concentration (Bmax) and dissociation equilibrium constant (Kd). Methods: Four rhesus monkeys underwent 12 scans with 11C-GR103545 on a PET scanner under baseline and self-blocking conditions. The injected mass was 0.042 ± 0.014 μg/kg for the baseline scans and ranged from 0.16 to 0.3 μg/kg for the self-blocking scans. The radiotracer was administered in a bolus-plus-infusion protocol, and cerebellum was used as the reference region in kinetic analysis. Binding potential (BPND) values were computed as [(CROI/CREF) − 1], where CROI and CREF are the mean of the radioactivity concentrations from 90 to 120 min after tracer administration in a given region of interest (ROI) and in the cerebellum. In 6 scans, arterial input functions and free fraction in plasma (fp) were measured. In addition, a 2-tissue-compartment model was used to compute the volume of distribution in the cerebellum (VT_REF), which was then used to estimate the free–to–nondisplaceable concentration ratio (fND) as fp/VT_REF. A Scatchard plot was used to estimate Bmax, and KdND = Kd/fND, the Kd value with respect to the cerebellar concentration. Individual data were first analyzed separately and then pooled together. When KdND was allowed to vary among ROIs, results were variable; therefore, KdND was constrained to be constant across ROIs, whereas Bmax was allowed to be ROI-dependent and animal-dependent. Results: A global estimate of 1.72 nM was obtained for KdND. Estimated Bmax ranged from 0.3 to 6.1 nM across ROIs and animals. The Kd estimate of 0.048 nM, obtained by correcting KdND by the factor fND, was in good agreement with the half maximal inhibitory concentration (IC50) of 0.018 nM determined from functional assays in rabbit vas deferens and inhibition constant (Ki) of 0.02 nM measured in radioligand competition assays using cloned human receptors. On the basis of these data, a suitable tracer dose of 0.02 μg/kg was selected for use in humans. Conclusion: The use of a bolus-plus-infusion protocol with the KOR agonist tracer 11C-GR103545 permitted the successful estimation of Bmax and KdND in vivo. On the basis of the estimated Kd value, a tracer dose of 1.4 μg (3.38 nmol) for an average body weight of 70 kg was chosen as the mass dose limit in human studies using this novel agonist radiotracer.