Michael Kapinos
Yale University
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Featured researches published by Michael Kapinos.
The Journal of Nuclear Medicine | 2015
Mika Naganawa; Ming-Qiang Zheng; Shannan Henry; Nabeel Nabulsi; Shu-fei Lin; Jim Ropchan; David Labaree; Soheila Najafzadeh; Michael Kapinos; Johannes Tauscher; Alexander Neumeister; Richard E. Carson; Yiyun Huang
11C-LY2795050 is a new antagonist PET radioligand for the κ opioid receptor (KOR). In this study, we assessed the reproducibility of the binding parameters of 11C-LY2795050 in healthy human subjects. Methods: Sixteen healthy subjects (11 men and 5 women) underwent 2 separate 90-min PET scans with arterial input function and plasma free fraction (fP) measurements. The 2-tissue-compartment model and multilinear analysis-1 were applied to calculate 5 outcome measures in 14 brain regions: distribution volume (VT), VT normalized by fP (VT/fP), and 3 binding potentials (nondisplaceable binding potential, binding potential relative to total plasma concentration, and binding potential relative to free plasma concentration: BPND, BPP, BPF, respectively). Since KOR is distributed ubiquitously throughout the brain, there are no suitable reference regions. We used a fixed fraction of individual cerebellar VT value (VT,CER) as the nondisplaceable VT (VND) (VND = VT,CER/1.17). The relative and absolute test–retest variability and intraclass correlation coefficient were evaluated for the outcome measures of 11C-LY2795050. Results: The test–retest variability of 11C-LY2795050 for VT was no more than 10% in any region and was 12% in the amygdala. For binding potential (BPND and BPP), the test–retest variability was good in regions of moderate and high KOR density (BPND > 0.4) and poor in regions of low density. Correction by fP (VT/fP or BPF) did not improve the test–retest performance. Conclusion: Our results suggest that quantification of 11C-LY2795050 imaging is reproducible and reliable in regions with moderate and high KOR density. Therefore, we conclude that this first antagonist radiotracer is highly useful for PET studies of KOR.
Synapse | 2015
Shu-fei Lin; David Labaree; Ming-Kai Chen; Daniel Holden; Jean-Dominique Gallezot; Michael Kapinos; Jo-ku Teng; Soheila Najafzadeh; Christophe Plisson; Eugenii Rabiner; Roger N. Gunn; Richard E. Carson; Yiyun Huang
[11C]MP‐10 is a potent and specific PET tracer previously shown to be suitable for imaging the phosphodiesterase 10A (PDE10A) in baboons with reversible kinetics and high specific binding. However, another report indicated that [11C]MP‐10 displayed seemingly irreversible kinetics in rhesus monkeys, potentially due to the presence of a radiolabeled metabolite capable of penetrating the blood‐brain‐barrier (BBB) into the brain. This study was designed to address the discrepancies between the species by re‐evaluating [11C]MP‐10 in vivo in rhesus monkey with baseline scans to assess tissue uptake kinetics and self‐blocking scans with unlabeled MP‐10 to determine binding specificity. Ex vivo studies with one rhesus monkey and 4 Sprague‐Dawley rats were also performed to investigate the presence of radiolabeled metabolites in the brain. Our results indicated that [11C]MP‐10 displayed reversible uptake kinetics in rhesus monkeys, albeit slower than in baboons. Administration of unlabeled MP‐10 reduced the binding of [11C]MP‐10 in a dose‐dependent manner in all brain regions including the cerebellum. Consequently, the cerebellum appeared not to be a suitable reference tissue in rhesus monkeys. Regional volume of distribution (VT) was mostly reliably derived with the multilinear analysis (MA1) method. In ex vivo studies in the monkey and rats only negligible amount of radiometabolites was seen in the brain of either species. In summary, results from the present study strongly support the suitability of [11C]MP‐10 as a radiotracer for PET imaging and quantification of PDE10A in nonhuman primates. Synapse 69:86–95, 2015.
Metabolism-clinical and Experimental | 2015
Janice J. Hwang; Catherine W. Yeckel; Jean-Dominique Gallezot; Renata Belfort-De Aguiar; Devrim Ersahin; Hong Gao; Michael Kapinos; Nabeel Nabulsi; Yiyun Huang; David Cheng; Richard E. Carson; Robert S. Sherwin; Yu-Shin Ding
INTRODUCTION Brown adipose tissue (BAT) plays a critical role in adaptive thermogenesis and is tightly regulated by the sympathetic nervous system (SNS). However, current BAT imaging modalities require cold stimulation and are often unreliable to detect BAT in the basal state, at room temperature (RT). We have shown previously that BAT can be detected in rodents under both RT and cold conditions with (11)C-MRB ((S,S)-(11)C-O-methylreboxetine), a highly selective ligand for the norepinephrine transporter (NET). Here, we evaluate this novel approach for BAT detection in adult humans under RT conditions. METHODS Ten healthy, Caucasian subjects (5 M: age 24.6±2.6, BMI 21.6±2.7kg/m(2); 5 F: age 25.4±2.1, BMI 22.1±1.0kg/m(2)) underwent (11)C-MRB PET-CT imaging for cervical/supraclavicular BAT under RT and cold-stimulated conditions (RPCM Cool vest; enthalpy 15°C) compared to (18)F-FDG PET-CT imaging. Uptake of (11)C-MRB, was quantified as the distribution volume ratio (DVR) using the occipital cortex as a low NET density reference region. Total body fat and lean body mass were assessed via bioelectrical impedance analysis. RESULTS As expected, (18)F-FDG uptake in BAT was difficult to identify at RT but easily detected with cold stimulation (p=0.01). In contrast, BAT (11)C-MRB uptake (also normalized for muscle) was equally evident under both RT and cold conditions (BAT DVR: RT 1.0±0.3 vs. cold 1.1±0.3, p=0.31; BAT/muscle DVR: RT 2.3±0.7 vs. cold 2.5±0.5, p=0.61). Importantly, BAT DVR and BAT/muscle DVR of (11)C-MRB at RT correlated positively with core body temperature (r=0.76, p=0.05 and r=0.92, p=0.004, respectively), a relationship not observed with (18)F-FDG (p=0.63). Furthermore, there were gender differences in (11)C-MRB uptake in response to cold (p=0.03), which reflected significant differences in the change in (11)C-MRB as a function of both body composition and body temperature. CONCLUSIONS Unlike (18)F-FDG, the uptake of (11)C-MRB in BAT offers a unique opportunity to investigate the role of BAT in humans under basal, room temperature conditions.
The Journal of Nuclear Medicine | 2014
Ming-Qiang Zheng; Su Jin Kim; Daniel Holden; Shu-fei Lin; Anne B. Need; Karen Rash; Vanessa N. Barth; Charles H. Mitch; Antonio Navarro; Michael Kapinos; Kathleen Maloney; Jim Ropchan; Richard E. Carson; Yiyun Huang
The κ-opioid receptors (KORs) are implicated in several neuropsychiatric diseases and addictive disorders. PET with radioligands provides a means to image the KOR in vivo and investigate its function in health and disease. The purpose of this study was to develop the selective KOR antagonist 11C-LY2459989 as a PET radioligand and characterize its imaging performance in nonhuman primates. Methods: LY2459989 was synthesized and assayed for in vitro binding to opioid receptors. Ex vivo studies in rodents were conducted to assess its potential as a tracer candidate. 11C-LY2459989 was synthesized by reaction of its iodophenyl precursor with 11C-cyanide, followed by partial hydrolysis of the resulting 11C-cyanophenyl intermediate. Imaging experiments with 11C-LY2459989 were performed in rhesus monkeys with arterial input function measurement. Imaging data were analyzed with kinetic models to derive in vivo binding parameters. Results: LY2459989 is a full antagonist with high binding affinity and selectivity for KOR (0.18, 7.68, and 91.3 nM, respectively, for κ, μ, and δ receptors). Ex vivo studies in rats indicated LY2459989 as an appropriate tracer candidate with high specific binding signals and confirmed its KOR binding selectivity in vivo. 11C-LY2459989 was synthesized in high radiochemical purity and good specific activity. In rhesus monkeys, 11C-LY2459989 displayed a fast rate of peripheral metabolism. Similarly, 11C-LY2459989 displayed fast uptake kinetics in the brain and an uptake pattern consistent with the distribution of KOR in primates. Pretreatment with naloxone (1 mg/kg, intravenously) resulted in a uniform distribution of radioactivity in the brain. Further, specific binding of 11C-LY2459989 was dose-dependently reduced by the selective KOR antagonist LY2456302 and the unlabeled LY2459989. Regional binding potential values derived from the multilinear analysis-1 (MA1) method, as a measure of in vivo specific binding signal, were 2.18, 1.39, 1.08, 1.04, 1.03, 0.59, 0.51, and 0.50, respectively, for the globus pallidus, cingulate cortex, insula, caudate, putamen, frontal cortex, temporal cortex, and thalamus. Conclusion: The novel PET radioligand 11C-LY2459989 displayed favorable pharmacokinetic properties, a specific and KOR-selective binding profile, and high specific binding signals in vivo, thus making it a promising PET imaging agent for KOR.
The Journal of Nuclear Medicine | 2017
Evan Baum; Zhengxin Cai; Frederic Bois; Daniel Holden; Shu-fei Lin; Teresa Lara-Jamie; Michael Kapinos; Yuanyuan Chen; Winnie Deuther-Conrad; Steffen Fischer; Sladjana Dukic-Stefanovic; Paul Bunse; Bernhard Wünsch; Peter Brust; Hongmei Jia; Yiyun Huang
The σ1 receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 18F-labeled spirocyclic piperidine-based PET radiotracers (18F-1 to 18F-4). Methods: Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity of 18F-2 and 18F-4. Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. Results: In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid for 18F-2 and 18F-4, and much slower for 18F-1 and 18F-3, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time–activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. 18F-4 showed greater differential uptake across brain regions and 3-fold-higher binding potential than 18F-2. SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (18F-2) and 95% (18F-4) of radiotracer binding. Conclusion: Tracers 18F-2 and 18F-4 displayed high brain uptake and fast tissue kinetics, with 18F-4 having higher specific binding signals than 18F-2 in the same monkey. Taken together, these data indicate that both 18F-2 and 18F-4 possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.
Molecular Imaging | 2017
Shu-fei Lin; Frederic Bois; Daniel Holden; Nabeel Nabulsi; Richard Pracitto; Hong Gao; Michael Kapinos; Jo-ku Teng; Anupama Shirali; Jim Ropchan; Richard E. Carson; Charles S. Elmore; Neil Vasdev; Yiyun Huang
The myriad physiological functions of γ-amino butyric acid (GABA) are mediated by the GABA-benzodiazepine receptor complex comprising of the GABAA, GABAB, and GABAC groups. The various GABAA subunits with region-specific distributions in the brain subserve different functional and physiological roles. For example, the sedative and anticonvulsive effects of classical benzodiazepines are attributed to the α1 subunit, and the α2 and α3 subunits mediate the anxiolytic effect. To optimize pharmacotherapies with improved efficacy and devoid of undesirable side effects for the treatment of anxiety disorders, subtype-selective imaging radiotracers are required to assess target engagement at GABA sites and determine the dose–receptor occupancy relationships. The goal of this work was to characterize, in nonhuman primates, the in vivo binding profile of a novel positron emission tomography (PET) radiotracer, [11C]ADO, which has been indicated to have functional selectivity for the GABAA α2/α3 subunits. High specific activity [11C]ADO was administrated to 3 rhesus monkeys, and PET scans of 120-minute duration were performed on the Focus-220 scanner. In the blood, [11C]ADO metabolized at a fairly rapid rate, with ∼36% of the parent tracer remaining at 30 minutes postinjection. Uptake levels of [11C]ADO in the brain were high (peak standardized uptake value of ∼3.0) and consistent with GABAA distribution, with highest activity levels in cortical areas, intermediate levels in cerebellum and thalamus, and lowest uptake in striatal regions and amygdala. Tissue kinetics was fast, with peak uptake in all brain regions within 20 minutes of tracer injection. The one-tissue compartment model provided good fits to regional time–activity curves and reliable measurement of kinetic parameters. The absolute test–retest variability of regional distribution volumes (V T) was low, ranging from 4.5% to 8.7%. Pretreatment with flumazenil (a subtype nonselective ligand, 0.2 mg/kg, intravenous [IV], n = 1), Ro15-4513 (an α5-selective ligand, 0.03 mg/kg, IV, n = 2), and zolpidem (an α1-selective ligand, 1.7 mg/kg, IV, n = 1) led to blockade of [11C]ADO binding by 96.5%, 52.5%, and 76.5%, respectively, indicating the in vivo binding specificity of the radiotracer. Using the nondisplaceable volume of distribution (V ND) determined from the blocking studies, specific binding signals, as measured by values of regional binding potential (BP ND), ranged from 0.6 to 4.4, which are comparable to those of [11C]flumazenil. In conclusion, [11C]ADO was demonstrated to be a specific radiotracer for the GABAA receptors with several favorable properties: high brain uptake, fast tissue kinetics, and high levels of specific binding in nonhuman primates. However, subtype selectivity in vivo is not obvious for the radiotracer, and thus, the search for subtype-selective GABAA radiotracers continues.
Journal of Cerebral Blood Flow and Metabolism | 2015
Yan Xia; Ming-Qiang Zheng; Daniel Holden; Shu-fei Lin; Michael Kapinos; Jim Ropchan; Jean-Dominique Gallezot; Yiyun Huang; Richard E. Carson
Glycine is a co-agonist of glutamate at the NMDA receptor. Glycine transporter 1 (GlyT1) inhibitors are reported to be potential therapeutic agents for schizophrenia. 18F-MK6577 is a new positron emission tomography (PET) radiotracer useful for imaging brain GlyT1 and its occupancy in humans. We devised a novel multi-infusion paradigm of radiolabeled and unlabeled compound and an iterative linear/nonlinear alternating fitting method to allow for the determination of in vivo affinity (Kd) and target concentration (Bmax) images, constraining Kd to be uniform across the brain. This paradigm was tested with 18F-MK6577 in baboons. Voxel-based analysis produced high quality Bmax images and reliable Kd estimates, and also suggested that the nondisplaceable distribution volume (VND) is not uniform throughout the brain. In vivo GlyT1 Kd was estimated to be 1.87 nmol/L for 18F-MK6577, and the rank order of GlyT1 distribution measured in the baboon brain was: high in the brainstem (133 nmol/L), medium in the cerebellum (83 nmol/L), and low in the cortex (30 nmol/L). These in vivo Kd and Bmax values agreed well with those determined in vitro, thus validating our novel multi-infusion approach.
The Journal of Nuclear Medicine | 2018
Songye Li; Zhengxin Cai; Ming-Qiang Zheng; Daniel Holden; Mika Naganawa; Shu-fei Lin; Jim Ropchan; David Labaree; Michael Kapinos; Teresa Lara-Jaime; Antonio Navarro; Yiyun Huang
The κ-opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18F-LY2459989 as the first 18F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11C-LY2459989. Methods: The novel radioligand 18F-LY2459989 was synthesized by 18F displacement of a nitro group or an iodonium ylide. PET scans in rhesus monkeys were obtained on a small-animal scanner to assess the pharmacokinetic and in vivo binding properties of the ligand. Metabolite-corrected arterial activity curves were measured and used as input functions in the analysis of brain time–activity curves and the calculation of binding parameters. Results: With the iodonium ylide precursor, 18F-LY2459989 was prepared at high radiochemical yield (36% ± 7% [mean ± SD]), radiochemical purity (>99%), and mean molar activity (1,175 GBq/μmol; n = 6). In monkeys, 18F-LY2459989 was metabolized at a moderate rate, with a parent fraction of approximately 35% at 30 min after injection. Fast and reversible kinetics were observed, with a regional peak uptake time of less than 20 min. Pretreatment with the selective KOR antagonist LY2456302 (0.1 mg/kg) decreased the activity level in regions with high levels of binding to that in the cerebellum, thus demonstrating the binding specificity and selectivity of 18F-LY2459989 in vivo. Regional time–activity curves were well fitted by the multilinear analysis 1 kinetic model to derive reliable estimates of regional distribution volumes. With the cerebellum as the reference region, regional binding potentials were calculated and ranked as follows: cingulate cortex > insula > caudate/putamen > frontal cortex > temporal cortex > thalamus, consistent with the reported KOR distribution in the monkey brain. Conclusion: The evaluation of 18F-LY2459989 in nonhuman primates demonstrated many attractive imaging properties: fast tissue kinetics, specific and selective binding to the KOR, and high specific binding signals. A side-by-side comparison of 18F-LY2459989 and 11C-LY2459989 indicated similar kinetic and binding profiles for the 2 radiotracers. Taken together, the results indicated that 18F-LY2459989 appears to be an excellent PET radiotracer for the imaging and quantification of the KOR in vivo.
Synapse | 2016
Ming-Qiang Zheng; Shu-fei Lin; Daniel Holden; Mika Naganawa; Jim Ropchan; Soheila Najafzaden; Michael Kapinos; Mike Tabriz; Richard E. Carson; Terence G. Hamill; Yiyun Huang
Glycine transporter type‐1 (GlyT1) has been proposed as a target for drug development for schizophrenia. PET imaging with a GlyT1 specific radiotracer will allow for the measurement of target occupancy of GlyT1 inhibitors, and for in vivo investigation of GlyT1 alterations in schizophrenia. We conducted a comparative evaluation of two GlyT1 radiotracers, [11C]GSK931145, and [18F]MK‐6577, in baboons. Two baboons were imaged with [11C]GSK931145 and [18F]MK‐6577. Blocking studies with GSK931145 (0.3 or 0.2 mg/kg) were conducted to determine the level of tracer specific binding. [11C]GSK931145 and [18F]MK‐6577 were synthesized in good yield and high specific activity. Moderately fast metabolism was observed for both tracers, with ∼30% of parent at 30 min post‐injection. In the brain, both radiotracers showed good uptake and distribution profiles consistent with regional GlyT1 densities. [18F]MK‐6577 displayed higher uptake and faster kinetics than [11C]GSK931145. Time activity curves were well described by the two‐tissue compartment model. Regional volume of distribution (VT) values were higher for [18F]MK‐6577 than [11C]GSK931145. Pretreatment with GSK931145 reduced tracer uptake to a homogeneous level throughout the brain, indicating in vivo binding specificity and lack of a reference region for both radiotracers. Linear regression analysis of VT estimates between tracers indicated higher specific binding for [18F]MK‐6577 than [11C]GSK931145, consistent with higher regional binding potential (BPND) values of [18F]MK‐6577 calculated using VT from the baseline scans and non‐displaceable distribution volume (VND) derived from blocking studies. [18F]MK‐6577 appears to be a superior radiotracer with higher brain uptake, faster kinetics, and higher specific binding signals than [11C]GSK931145. Synapse 70:112–120, 2016.
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging | 2016
Deepak Cyril D’Souza; Jose Cortes-Briones; Mohini Ranganathan; Halle Thurnauer; Gina Creatura; Toral Surti; Beata Planeta; Alexander Neumeister; Brian Pittman; Marc D. Normandin; Michael Kapinos; Jim Ropchan; Yiyun Huang; Richard E. Carson; Patrick D. Skosnik