Kinetic modeling and test-retest reproducibility of 11C-EKAP and 11C-FEKAP, novel agonist radiotracers for PET imaging of the kappa opioid receptor in humans.

The kappa 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 to KOR, it displayed slow kinetics and relatively large test-retest variability (TRV) of distribution volume (V T) estimates (15%). Therefore we set out to develop two novel KOR agonist radiotracers, (11)C-EKAP and (11)C-FEKAP, and in nonhuman primates, both tracers exhibited faster kinetics 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 (TACs) were generated for 14 regions of interest. One- and two-tissue compartment models (1TC, 2TC) and the multilinear analysis-1 (MA1) method were applied to the regional TACs to calculate V T Time-stability of V T values and test-retest reproducibility were evaluated. Levels of specific binding, as measured by the non-displaceable binding potential (BP ND) for the three tracers ((11)C-EKAP, (11)C-FEKAP and (11)C-GR103545), were compared using a graphical method. Results: For both tracers, regional TACs were fitted well with the 2TC model and MA1 method (t*=20min), but not with the 1TC model. Given unreliably estimated parameters in several fits with the 2TC model and a good match between V T values from MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 V T values were highest for (11)C-GR103545, followed by (11)C-EKAP, then (11)C-FEKAP. Minimum scan time for stable V T measurement was 90 and 110min for (11)C-EKAP and (11)C-FEKAP, respectively, compared with 140min for (11)C-GR103545. The mean absolute TRV 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 ~25% lower for (11)C-EKAP. Conclusion: The two novel KOR agonist tracers showed faster tissue kinetics than (11)C-GR103545. Even with slightly lower BP ND, (11)C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, based on the shorter minimum scan time and excellent test-retest.