TY - JOUR T1 - Kinetic Modeling and Test–Retest Reproducibility of <sup>11</sup>C-EKAP and <sup>11</sup>C-FEKAP, Novel Agonist Radiotracers for PET Imaging of the κ-Opioid Receptor in Humans JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1636 LP - 1642 DO - 10.2967/jnumed.119.227694 VL - 61 IS - 11 AU - Mika Naganawa AU - Songye Li AU - Nabeel Nabulsi AU - Shu-fei Lin AU - David Labaree AU - Jim Ropchan AU - Hong Gao AU - Michael Mei AU - Shannan Henry AU - David Matuskey AU - Richard E. Carson AU - Yiyun Huang Y1 - 2020/11/01 UR - http://jnm.snmjournals.org/content/61/11/1636.abstract N2 - 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 (VT) 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 VT. The time stability of VT and test–retest reproducibility were evaluated. Levels of specific binding, as measured by the nondisplaceable binding potential (BPND) 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 VT match between MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 VT was highest for 11C-GR103545, followed by 11C-EKAP and then 11C-FEKAP. The minimum scan time for stable VT 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 VT estimates was 7% and 18% for 11C-EKAP and 11C-FEKAP, respectively. BPND 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 BPND, 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 VT. ER -