In Vitro and In Vivo Characterization of Two C-11-Labeled PET Tracers for Vesicular Acetylcholine Transporter
| Autor: | Xiang Zhang, Hongjun Jin, Zhude Tu, Ruike Wang, Prashanth K. Padakanti, Stanley M. Parsons, Joel S. Perlmutter, Junfeng Li, Hubert P. Flores, Jinquan Cui |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Cancer Research Pathology medicine.medical_specialty Vesamicol Physiology Vesicular Acetylcholine Transport Proteins Clinical Sciences PET imaging Biology Article Rats Sprague-Dawley chemistry.chemical_compound In vivo Vesicular acetylcholine transporter medicine Animals Tissue Distribution Radiology Nuclear Medicine and imaging Radioactive Tracers Cholinergic neuron Pet tracer Brain Chemistry Carbon Isotopes Radiotracer Neurosciences Brain Alzheimer's disease In vitro Rats Brain Disorders Biomarker (cell) Cell biology Macaca fascicularis Nuclear Medicine & Medical Imaging VAChT Oncology chemistry Neurological Autoradiography Biomedical Imaging Sprague-Dawley Radiopharmaceuticals |
| Zdroj: | Molecular imaging and biology, vol 16, iss 6 |
| ISSN: | 1860-2002 1536-1632 |
| DOI: | 10.1007/s11307-014-0749-9 |
| Popis: | PurposeThe vesicular acetylcholine transporter (VAChT) is a specific biomarker for imaging presynaptic cholinergic neurons. Herein, two potent and selective (11)C-labeled VAChT inhibitors were evaluated in rodents and nonhuman primates for imaging VAChT in vivo.ProceduresFor both (-)-[(11)C]2 and (-)-[(11)C]6, biodistribution, autoradiography, and metabolism studies were performed in male Sprague Dawley rats. Positron emission tomography (PET) brain studies with (-)-[(11)C]2 were performed in adult male cynomolgus macaques; 2 h dynamic data was acquired, and the regions of interest were drawn by co-registration of the PET images with the MRI.ResultsThe resolved enantiomers (-)-2 and (-)-6 were very potent and selective for VAChT in vitro (K i 35-fold selectivity for VAChT vs. σ receptors); both radioligands, (-)-[(11)C]2 and (-)-[(11)C]6, demonstrated high accumulation in the VAChT-enriched striatum of rats. (-)-[(11)C]2 had a higher striatum to cerebellum ratio of 2.4-fold at 60 min; at 30 min, striatal uptake reached 0.550 ± 0.086 %ID/g. Uptake was also specific and selective; following pretreatment with (±)-2, striatal uptake of (-)-[(11)C]2 in rats at 30 min decreased by 50 %, while pretreatment with a potent sigma ligand had no significant effect on striatal uptake in rats. In addition, (-)-[(11)C]2 displayed favorable in vivo stability in rat blood and brain. PET studies of (-)-[(11)C]2 in nonhuman primates indicate that it readily crosses the blood-brain barrier (BBB) and provides clear visualization of the striatum; striatal uptake reaches the maximum at 60 min, at which time the target to nontarget ratio reached ~2-fold.ConclusionsThe radioligand (-)-[(11)C]2 has high potential to be a suitable PET radioligand for imaging VAChT in the brain of living subjects. |
| Databáze: | OpenAIRE |
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