Biology subjects

Belov, V.

Publications and source records attributed to Belov, V..

3 recordsLinked to original sources

bioRxiv2022

Radiochemical Synthesis and Evaluation of 3-methyl-4-aminopyridine in Rodents and Non-Human Primates for Imaging Potassium Channels in the CNS

Demyelination, the loss of the insulating sheath of neurons, causes failed or slowed neuronal conduction and contributes to the neurological symptoms in multiple sclerosis, traumatic brain and spinal cord injuries, stroke, and dementia. In demyelinated neurons, the axonal potassium channels Kv1.1 and Kv1.2, generally under the myelin sheath, become exposed and upregulated. Therefore, imaging these channels using positron emission tomography can provide valuable information for disease diagnosis and monitoring. Here, we describe the novel tracer for Kv1 channels [11C]3-methyl-4-aminopyridine ([11C]3Me4AP). [11C]3Me4AP was efficiently synthesized via Pd(0)-Cu(I) co-mediated Stille cross-coupling of a stannyl precursor containing a free amino group. Evaluation of its imaging properties in rats and nonhuman primates showed that [11C]3Me4AP has a moderate brain permeability and slow kinetics. Additional evaluation in monkeys showed that the tracer is metabolically stable and that a 1-tissue compartment model can accurately model the regional brain time-activity curves. Compared to the related tracers [18F]3-fluoro-4-aminopyridine ([18F]3F4AP) and [11C]3-methoxy-4-aminopyridine ([11C]3MeO4AP), [11C]3Me4AP shows lower initial brain uptake, which indicates reduced permeability to the blood-brain-barrier and slower kinetics, suggesting higher binding affinity consistent with in vitro studies. While the slow kinetics and strong binding affinity resulted in a tracer with less favorable properties for imaging the brain than its predecessors, these properties may make 3Me4AP useful as a therapeutic.

neuroscience↗

bioRxiv2022

Development of a PET radioligand for α2δ-1 subunit of calcium channels for imaging neuropathic pain

Neuropathic pain affects 7-10% of the adult population. Being able to accurately monitor biological changes underlying neuropathic pain will improve our understanding of neuropathic pain mechanisms and facilitate the development of novel therapeutics. Positron emission tomography (PET) is a noninvasive molecular imaging technique that can provide quantitative information of biochemical changes at the whole-body level by using radiolabeled ligands. One important biological change underlying the development of neuropathic pain is the overexpression of 2{delta}-1 subunit of voltage-dependent calcium channels (the target of gabapentin). Thus, we hypothesized that a radiolabeled form of gabapentin may allow imaging changes in 2{delta}-1 for monitoring the underlying pathophysiology of neuropathic pain. Here, we report the development of two 18F-labeled derivatives of gabapentin (trans-4-[18F]fluorogabapentin and cis-4-[18F]fluorogabapentin) and their evaluation in healthy rats and a rat model of neuropathic pain (spinal nerve ligation model). Both isomers were found to selectively bind to the 2{delta}-1 receptor with trans-4-[18F]fluorogabapentin having a higher affinity. Both tracers displayed around 1.5- to 2-fold increased uptake in injured nerves over the contralateral uninjured nerves when measured by gamma counting ex vivo. Although the small size of the nerves and the signal from surrounding muscle prevented visualizing these changes using PET, this work demonstrates that fluorinated derivatives of gabapentin retain binding to 2{delta}-1 and that their radiolabeled forms can be used to detect pathological changes in vitro and ex vivo. Furthermore, this work confirms that 2{delta}-1 is a promising target for imaging specific features of neuropathic pain.

neuroscience↗

bioRxiv2021

High frequency rTMS modulates functional connectivity nodes and boundaries differently in the human brain

Repetitive transcranial magnetic stimulation (rTMS) has gained considerable importance in the treatment of neuropsychiatric disorders, including major depression. However, it is not yet understood how rTMS alters brains functional connectivity. Here we report changes in functional connectivity captured by resting state functional magnetic resonance imaging (rsfMRI) within the first hour after 10Hz rTMS. We apply subject-specific parcellation schemes to detect changes (1) in network nodes, where the strongest functional connectivity of regions is observed, and (2) in network boundaries, where functional transitions between regions occur. We use support vector machines (SVM), a widely used machine learning algorithm that is robust and effective for the classification and characterization of time intervals of changes in node and boundary maps. Our results reveal that changes in connectivity at the boundaries are slower and more complex than in those observed in the nodes, but of similar magnitude according to accuracy confidence intervals. These results were strongest in the posterior cingulate cortex and precuneus. As network boundaries are indeed under-investigated in comparison to nodes in connectomics research, our results highlight their contribution to functional adjustments to rTMS.

neuroscience↗