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

1区 · 医学

Article

作者: Mei, Michael ; Nabulsi, Nabeel ; Labaree, David ; Gao, Hong ; Matuskey, David ; Carson, Richard E ; Naganawa, Mika ; Li, Songye ; Huang, Yiyun ; Ropchan, Jim ; Henry, Shannan ; Lin, Shu-Fei

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.

2019-07-01·Journal of Nuclear Medicine1区 · 医学

Development and In Vivo Evaluation of a κ-Opioid Receptor Agonist as a PET Radiotracer with Superior Imaging Characteristics

1区 · 医学

Article

作者: Labaree, David ; Gao, Hong ; Naganawa, Mika ; Kim, Sujin ; Huang, Yiyun ; Li, Songye ; Kapinos, Michael ; Zheng, Ming-Qiang

Studies have shown κ-opioid receptor (KOR) abnormalities in addictive disorders, other central nervous system diseases, and Alzheimer's disease. We have developed the first set of agonist ¹¹C-GR103545 and antagonist ¹¹C-LY2795050 radiotracers for PET imaging of KOR in humans. Nonetheless, ¹¹C-GR103545 displays protracted uptake kinetics and is not an optimal radiotracer. Here, we report the development and evaluation of ¹¹C-methyl-(R)-4-(2-(3,4-dichlorophenyl)acetyl)-3-((diethylamino)methyl)piperazine-1-carboxylate (¹¹C-EKAP) and its comparison with ¹¹C-GR103545. Methods: EKAP was synthesized and assayed for in vitro binding affinities and then radiolabeled. PET studies were performed on rhesus monkeys. Blocking studies were performed with naloxone and the selective KOR antagonists LY2795050 and LY2456302. Arterial input functions were generated for use in kinetic modeling. Brain TACs were analyzed with multilinear analysis 1 to derive binding parameters. Results: EKAP has high KOR affinity (inhibition constant, 0.28 nM) and good selectivity in vitro. ¹¹C-EKAP was prepared in good radiochemical purity. ¹¹C-EKAP rapidly metabolized in plasma and displayed fast and reversible kinetics in brain, with peak uptake at less than 20 min after injection. Preblocking with naloxone (1 mg/kg) or LY2795050 (0.2 mg/kg) produced 84%-89% receptor occupancy, whereas LY2456302 (0.05 and 0.3 mg/kg) dose-dependently reduced ¹¹C-EKAP-specific binding, thus demonstrating its binding specificity and selectivity in vivo. Mean multilinear analysis 1-derived nondisplaceable binding potential values were 1.74, 1.79, 1.46, 0.80, and 0.77 for cingulate cortex, globus pallidus, insula, striatum, and frontal cortex, respectively, consistent with the known KOR distribution in primate brains. Conclusion: We have successfully developed ¹¹C-EKAP as a KOR agonist tracer with dual attractive imaging properties of fast uptake kinetics and high specific binding in vivo.

2019-04-01·Molecular Pharmaceutics2区 · 医学

Novel Kappa Opioid Receptor Agonist as Improved PET Radiotracer: Development and in Vivo Evaluation

2区 · 医学

Article

作者: Pracitto, Richard ; Shirali, Anupama ; Teng, Jo-Ku ; Ropchan, Jim ; Naganawa, Mika ; Li, Songye ; Zheng, Ming-Qiang ; Gao, Hong ; Lin, Shu-fei ; Huang, Yiyun

The kappa opioid receptor (KOR) is involved in depression, alcoholism, and drug abuse. The current agonist radiotracer ¹¹C-GR103545 is not ideal for imaging KOR due to its slow tissue kinetics in human. The aim of our project was to develop novel KOR agonist radiotracers with improved imaging properties. A novel compound FEKAP ((( R))-4-(2-(3,4-dichlorophenyl)acetyl)-3-((ethyl(2-fluoroethyl)amino)methyl) piperazine-1-carboxylate) was designed, synthesized, and assayed for in vitro binding affinities. It was then radiolabeled and evaluated in rhesus monkeys. Baseline and blocking scans were conducted on a Focus-220 scanner to assess binding specificity and selectivity. Metabolite-corrected arterial activities over time were measured and used as input functions to analyze the brain regional time-activity curves and derive kinetic and binding parameters with kinetic modeling. FEKAP displayed high KOR binding affinity ( K_i = 0.43 nM) and selectivity (17-fold over mu opioid receptor and 323-fold over delta opioid receptor) in vitro. ¹¹C-FEKAP was prepared in high molar activity (mean of 718 GBq/μmol, n = 19) and >99% radiochemical purity. In monkeys, ¹¹C-FEKAP metabolized fairly fast, with ∼31% of intact parent fraction at 30 min post-injection. In the brain, it exhibited fast and reversible kinetics with good uptake. Pretreatment with the nonselective opioid receptor antagonist naloxone (1 mg/kg) decreased uptake in high binding regions to the level in the cerebellum, and the selective KOR antagonist LY2456302 (0.02 and 0.1 mg/kg) reduced ¹¹C-FEKAP specific binding in a dose-dependent manner. As a measure of specific binding signals, the mean binding potential ( BP_ND) values of ¹¹C-FEKAP derived from the multilinear analysis-1 (MA1) method were greater than 0.5 for all regions, except for the thalamus. The novel KOR agonist tracer ¹¹C-FEKAP demonstrated binding specificity and selectivity in vivo and exhibited attractive properties of fast tissue kinetics and high specific binding.

100 项与 11C-FEKAP 相关的药物交易

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