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Development and <i>in vivo</i> evaluation of a novel kappa opioid receptor agonist as PET radiotracer with superior imaging characteristics
摘要： Studies have shown kappa 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 positron emission tomography imaging of KOR in human. Nonetheless, 11C-GR103545 displays protracted uptake kinetics and is not an optimal radiotracer. Here we report the development and evaluation of 11C-EKAP and its comparison with 11C-GR103545. Methods: EKAP was synthesized and assayed for in vitro binding affinities, then radiolabeled with 11C-CH3OTf. PET studies were carried out in 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 time-activity curves were analyzed with the multilinear analysis 1 (MA1) method to derive binding parameters. Results: EKAP has high KOR affinity (Ki = 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 < 20 min post-injection. Pre-blocking with naloxone (1 mg/kg) or LY2795050 (0.2 mg/kg) produced 84-89% receptor occupancy, while LY2456302 (0.05 & 0.3 mg/kg) dose-dependently reduced 11C-EKAP specific binding, thus demonstrating its binding specificity and selectivity in vivo. Mean MA1-derived BPND values were 1.74, 1.79, 1.46, 0.80 and 0.77 for cingulate cortex, globus pallidus, insula, striatum and frontal cortex, consistent with the known KOR distribution in primate brains. Conclusions: We have successfully developed 11C-EKAP as a novel KOR agonist tracer with dual attractive imaging properties of fast uptake kinetics and high specific binding in vivo.
关键词： 11C-EKAP,PET radiotracer,agonist,non-human primates,kappa opioid receptor
更新于2025-09-23 15:22:29
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Synthesis and <i>in vivo</i> evaluation of a novel PET radiotracer for imaging of synaptic vesicle glycoprotein 2A (SV2A) in non-human primates
摘要： Structural disruption and alterations of synapses are associated with many brain disorders, including Alzheimer’s disease, epilepsy, depression and schizophrenia. We have previously developed the PET radiotracer 11C-UCB-J for imaging and quantification of synaptic vesicle glycoprotein 2A (SV2A) and synaptic density in non-human primates and humans. Here we report the synthesis of a novel radiotracer 18F-SDM-8 and its in vivo evaluation in rhesus monkeys. The in vitro binding assay of SDM-8 showed high SV2A binding affinity (Ki = 0.58 nM). 18F-SDM-8 was prepared in high molar activity (241.7 MBq/nmol) and radiochemical purity (> 98%). In the brain, 18F-SDM-8 displayed very high uptake with peak standardized uptake value greater than 8, and fast and reversible kinetics. A displacement study with levetiracetam and blocking studies with UCB-J and levetiracetam demonstrated its binding reversibility and specificity towards SV2A. Regional binding potential values were calculated and ranged from 0.8 in the brainstem to 4.5 in the cingulate cortex. Comparing to 11C-UCB-J, 18F-SDM-8 displayed the same attractive imaging properties: very high brain uptake, appropriate tissue kinetics, and high levels of specific binding. Given the longer half-life of F-18 and the feasibility for central production and multi-site distribution, 18F-SDM-8 holds promise as an excellent radiotracer for SV2A and as a biomarker for synaptic density measurement in neurodegenerative diseases and psychiatric disorders.
关键词： UCB-J,18F-SDM-8,PET,SV2A,non-human primates,synaptic density
更新于2025-09-23 15:21:21
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Behavioural responses to a photovoltaic subretinal prosthesis implanted in non-human primates
摘要： Retinal dystrophies and age-related macular degeneration related to photoreceptor degeneration can cause blindness. In blind patients, although the electrical activation of the residual retinal circuit can provide useful artificial visual perception, the resolutions of current retinal prostheses have been limited either by large electrodes or small numbers of pixels. Here we report the evaluation, in three awake non-human primates, of a previously reported near-infrared-light-sensitive photovoltaic subretinal prosthesis. We show that multipixel stimulation of the prosthesis within radiation safety limits enabled eye tracking in the animals, that they responded to stimulations directed at the implant with repeated saccades and that the implant-induced responses were present two years after device implantation. Our findings pave the way for the clinical evaluation of the prosthesis in patients affected by dry atrophic age-related macular degeneration.
关键词： artificial visual perception,non-human primates,photovoltaic subretinal prosthesis,age-related macular degeneration,retinal prostheses
更新于2025-09-11 14:15:04