Kinetic Modeling and Test–Retest Reproducibility of ¹¹C-EKAP and ¹¹C-FEKAP, Novel Agonist Radiotracers for PET Imaging of the κ-Opioid Receptor in Humans

Abstract

The κ-opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, ¹¹C-GR103545, for PET imaging of KOR in humans. Although ¹¹C-GR103545 showed high brain uptake, good binding specificity, and selectivity for KOR, it displayed slow kinetics and relatively large test–retest variability of total distribution volume (V_T) estimates (15%). Therefore, we set out to develop 2 novel KOR agonist radiotracers, ¹¹C-EKAP and ¹¹C-FEKAP. In nonhuman primates, both tracers exhibited faster kinetics than ¹¹C-GR103545 and comparable binding parameters to ¹¹C-GR103545. The aim of this study was to assess their kinetic and binding properties in humans. Methods: Six healthy subjects underwent 120-min test–retest PET scans with both ¹¹C-EKAP and ¹¹C-FEKAP. Metabolite-corrected arterial input functions were measured. Regional time–activity curves were generated for 14 regions of interest. One-tissue-compartment and 2-tissue-compartment (2TC) models and the multilinear analysis-1 (MA1) method were applied to the regional time–activity curves to calculate V_T. The time stability of V_T and test–retest reproducibility were evaluated. Levels of specific binding, as measured by the nondisplaceable binding potential (BP_ND) for the 3 tracers (¹¹C-EKAP, ¹¹C-FEKAP, and ¹¹C-GR103545), were compared using a graphical method. Results: For both tracers, regional time–activity curves were fitted well with the 2TC model and MA1 method (t* = 20 min) but not with the 1-tissue-compartment model. Given the unreliably estimated parameters in several fits with the 2TC model and a good V_T match between MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 V_T was highest for ¹¹C-GR103545, followed by ¹¹C-EKAP and then ¹¹C-FEKAP. The minimum scan time for stable V_T measurement was 90 and 110 min for ¹¹C-EKAP and ¹¹C-FEKAP, respectively, compared with 140 min for ¹¹C-GR103545. The mean absolute test–retest variability in MA1 V_T estimates was 7% and 18% for ¹¹C-EKAP and ¹¹C-FEKAP, respectively. BP_ND levels were similar for ¹¹C-FEKAP and ¹¹C-GR103545 but were about 25% lower for ¹¹C-EKAP. Conclusion: The 2 novel KOR agonist tracers showed faster tissue kinetics than ¹¹C-GR103545. Even with a slightly lower BP_ND, ¹¹C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, on the basis of the shorter minimum scan time and the excellent test–retest reproducibility of regional V_T.