Determination of the In Vivo Selectivity of a New κ-Opioid Receptor Antagonist PET Tracer ¹¹C-LY2795050 in the Rhesus Monkey

Abstract

[11C]LY2795050 is a novel kappa-selective antagonist PET tracer. The in vitro binding affinities (Ki) of LY2795050 at the kappa opioid (KOR) and mu opioid (MOR) receptors are 0.72 and 25.8 nM, respectively. Thus, the in vitro KOR/MOR binding selectivity is about 36:1. Our goal in this study was to determine the in vivo selectivity of this new KOR antagonist tracer in the monkey. Methods To estimate ED50 value of LY2795050 at the MOR and KOR sites, two series of blocking experiments were performed in three rhesus monkeys using [11C]LY2795050 and [11C]carfentanil with co-injections of various doses of unlabeled LY2795050. Kinetic modeling was applied to calculate regional binding potential (BPND), and one- and two-site binding curves were fitted to these data to measure [11C]LY2795050 binding selectivity. Results LY2795050 ED50 at MOR was 119 μg/kg based on a one-site model for [11C]carfentanil. The one-site binding model was also deemed sufficient to describe the specific binding of [11C]LY2795050 at KOR. The ED50 at KOR estimated from the one-site model was 15.6 μg/kg. Thus the ED50 ratio for MOR:KOR was 7.6. Conclusion The in vivo selectivity of [11C]LY2795050 for KOR over MOR is 7.6. [11C]LY2795050 has 4.7-fold lower selectivity at KOR over MOR in vivo as compared to in vitro. Nevertheless, based on our finding in vivo, 88 % of the PET-observed specific binding of [11C]LY2795050 under baseline condition will be due to binding of the tracer at the KOR site in a region with similar prevalence of KOR and MOR. We conclude that [11C]LY2795050 is sufficiently selective for KOR over MOR in vivo to be considered an appropriate probe for studying the kappa opioid receptor with PET.

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

“…Using the in vitro (0.72 nmol/L (9)) and in vivo (0.028 nmol/L (12)) K D values, the occupancy by carrier mass in all scans was calculated as <0.2% and <3%, respectively. In our previous study in rhesus monkeys (11), the LY2795050 ED 50 at KOR was estimated as 15.6 μg/kg. Using this ED 50 value, the occupancy by LY2795050 was < 1.5% in all scans.…”

“…This new tracer has been examined in both nonhuman primates (10, 11) and human subjects (12). Our previous analysis of human imaging data found that 150 mg oral dose of naltrexone blocked ~90% KOR across all brain regions, which suggests the absence of a suitable reference region for 11 C-LY2795050 in the human brain, and that the lowest inter-subject variability in three versions of binding potential ( BP ND , BP P , BP F ) was observed when the non-displaceable distribution volume ( V ND ) was estimated as a fixed fraction of cerebellum V T ( V T , CER = 1.17 V ND ).…”

Opioid system and human emotions

“…Most human studies reviewed here pertain to the μ system, although animal studies have established that different types of opioid receptors have distinct influences on mood‐related processes (Lutz and Kieffer, ). Accordingly, future human studies should exploit advances in PET radiochemistry and address the contribution of δ (Madar et al, ) and κ (Kim et al, ; Vijay et al, ) receptors to emotions. Finally, inducing emotions in human subjects in the laboratory is far from straightforward.…”

PET Neurochemical Imaging Modes

“…LY2795050 is a part of a new class of kappa opioid receptor (KOR) antagonist drugs and was reported to have good selectivity for KOR over the mu opioid receptor (MOR) (36:1 KOR:MOR) in a cellular assay (Mitch et al, 2011). To determine the in vivo selectivity for this drug, a PET occupancy study was conducted in rhesus monkeys, utilizing radiolabeled [ 11 C]LY2795050 (KOR radiotracer) and [ 11 C]carfentanil (MOR radiotracer) to assess opioid subtype selectivity (KOR:MOR) (Kim et al, 2013). Animals were treated with the KOR antagonist drug LY2795050 at six doses (1.6 – 400 µg/kg, i.v.)…”