Test–Retest Reproducibility of Binding Parameters in Humans with ¹¹C-LY2795050, an Antagonist PET Radiotracer for the κ Opioid Receptor

Abstract

11C-LY2795050 is a new antagonist PET radioligand for the kappa opioid receptor (KOR). In this study, we assessed the reproducibility of the binding parameters of 11C-LY2795050 in healthy human subjects. Methods Sixteen healthy subjects (11 men, 5 women) underwent two separate 90-min PET scans with arterial input function and plasma free fraction measurements. The two-tissue compartment model and multilinear analysis-1 were applied to calculate five outcome measures in 14 brain regions: distribution volume (VT), distribution volume normalized by plasma free fraction (VT/fP), and three binding potentials (BPND, BPP, BPF). Since KOR is distributed ubiquitously throughout the brain, there are no suitable reference regions. We used a fixed fraction of individual cerebellum VT value as the non-displaceable distribution volume VND (= VT CER/1.17). The relative and absolute test-retest variability and intra-class correlation coefficient were evaluated for the outcome measures of 11C-LY2795050. Results The test-retest variability of 11C-LY2795050 for VT was ≤ 10% in all regions, and 12% in the amygdala. For binding potentials (BPND and BPP), the test-retest variability was good in regions of moderate and high KOR density (BPND > 0.4) and poor in regions of low density. Correction by fP (VT/fP or BPF) did not improve the test-retest performance. Conclusion Our results suggest that quantification of 11C-LY2795050 imaging is reproducible and reliable in the regions with moderate and high KOR density. Therefore we conclude that this first antagonist radiotracer is highly useful for PET studies of KOR.

11CO bonds made easily for positron emission tomography radiopharmaceuticals

“…The κ-opioid receptor (KOR) antagonist [ 11 C]LY2795050 was evaluated in non-human primates to determine metabolism, distribution, target selectivity and specificity of radiotracer uptake. 207,208 [ 11 C]LY2795050 has since been translated to human KOR neuroimaging studies in normal 169,170 and diseased states. 209 Furthermore, this strategy and method for radiolabeling has proven useful in development of a second-generation KOR antagonist PET radiotracer with improved KOR selectivity and binding, [ 11 C]LY2459989.…”

Receptor Occupancy of the -Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050

“…The primary aim of this study was to demonstrate brain penetration and KOR target engagement after single oral doses of LY2456302 in healthy human subjects. KOR occupancy was assessed using the KOR specific antagonist radiotracer 11 C-LY2795050 Naganawa et al, 2014Naganawa et al, , 2015 and positron emission tomography (PET) across a range of doses (0.5-25 mg) that have been demonstrated to be safe and well tolerated in a previous study (Lowe et al, 2014). We measured RO at multiple doses and postdosing times, and characterized the relationship between LY2456302 plasma concentrations and KOR occupancy.…”

[11C]arachidonic acid incorporation measurement in human brain: Optimization for clinical use

“…The range of average PD R values obtained for K* across 10 ROIs (6.7– 13.9%), using either method of input function estimation with PBMC, were comparable or superior to test‐retest data reported for binding potentials or volumes of distribution (V T ) of other PET radiotracers in use. For example, average reported PD R values are 20.7% (BP F ), 17.2% (BP P ), and 16.5%5 (BP ND ) for [ 11 C]DASB (Ogden et al ); 9.90% (BP F ) for [ 11 C]CUMI‐101 (Milak et al ); from 9.2% to 15.6% (BP P ) for [ 11 C]PE2I (DeLorenzo, Kumar, Zanderigo, Mann, & Parsey, ); 16.9% (V T ) for [ 11 C]PBR28 (Collste et al ); and no >12% (V T ) for [ 11 C]LY2795050 (Naganawa et al ). Moreover, this level of repeatability was attained with 6 weeks occurring between test and retest, in contrast to more standard same‐day scan repetition.…”