Kinetic Modeling and Test-Retest Reproducibility of 11 C-EKAP and 11 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, ¹¹ C-GR103545, for PET imaging of KOR in humans. Although ¹¹ 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 ( V _T ) estimates (15%). Therefore, we set out to develop 2 novel KOR agonist radiotracers, ¹¹ C-EKAP and ¹¹ C-FEKAP. In nonhuman primates, both tracers exhibited faster kinetics than ¹¹ C-GR103545 and comparable binding parameters to ¹¹ C-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 ¹¹ C-EKAP and ¹¹ 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 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 ( ¹¹ C-EKAP, ¹¹ C-FEKAP, and ¹¹ C-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 ¹¹ C-GR103545, followed by ¹¹ C-EKAP and then ¹¹ C-FEKAP. The minimum scan time for stable V _T measurement was 90 and 110 min for ¹¹ C-EKAP and ¹¹ C-FEKAP, respectively, compared with 140 min for ¹¹ C-GR103545. The mean absolute test-retest variability in MA1 V _T estimates was 7% and 18% for ¹¹ C-EKAP and ¹¹ C-FEKAP, respectively. BP _ND levels were similar for ¹¹ C-FEKAP and ¹¹ C-GR103545 but were about 25% lower for ¹¹ C-EKAP. Conclusion: The 2 novel KOR agonist tracers showed faster tissue kinetics than ¹¹ C-GR103545. Even with a slightly lower BP _ND , ¹¹ 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 V _T .
(© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)