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

The κ-opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, C-GR103545, for PET imaging of KOR in humans. Although C-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 () estimates (15%). Therefore, we set out to develop 2 novel KOR agonist radiotracers, C-EKAP and C-FEKAP. In nonhuman primates, both tracers exhibited faster kinetics than C-GR103545 and comparable binding parameters to C-GR103545. The aim of this study was to assess their kinetic and binding properties in humans. Six healthy subjects underwent 120-min test-retest PET scans with both C-EKAP and C-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 The time stability of and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the nondisplaceable binding potential () for the 3 tracers (C-EKAP, C-FEKAP, and C-GR103545), were compared using a graphical method. For both tracers, regional time-activity curves were fitted well with the 2TC model and MA1 method (* = 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 match between MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 was highest for C-GR103545, followed by C-EKAP and then C-FEKAP. The minimum scan time for stable measurement was 90 and 110 min for C-EKAP and C-FEKAP, respectively, compared with 140 min for C-GR103545. The mean absolute test-retest variability in MA1 estimates was 7% and 18% for C-EKAP and C-FEKAP, respectively. levels were similar for C-FEKAP and C-GR103545 but were about 25% lower for C-EKAP. The 2 novel KOR agonist tracers showed faster tissue kinetics than C-GR103545. Even with a slightly lower , C-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 .