Biology subjects

Afshar, S.

Publications and source records attributed to Afshar, S..

5 recordsLinked to original sources

bioRxiv2021

Design, synthesis, and characterization of mG2P026 as a high contrast PET imaging ligand for metabotropic glutamate receptor 2

An array of triazolopyridines based on JNJ-46356479 (6) were synthesized as potential PET imaging ligands for metabotropic glutamate receptor 2 (mGluR2) in the brain. The selected candidates 8-11 featured an enhanced positive allosteric modulator (PAM) activity (37-fold max.) and an apparent mGluR2 agonist activity (25-fold max.) compared to compound 6. Radiolabeling of compounds 8 and 9 (also named mG2P026) was achieved via the Cu(I)-mediated radiofluorination in the automated TRACERLabTM FXF-N platform. Both [18F]8 and [18F]9 were obtained with satisfactory radiochemical yields (> 5%, non-decay corrected), high molar activity (> 180 GBq/mol), and excellent chemical and radiochemical purities (> 98%). Preliminary characterization of [18F]8 and [18F]9 in rats confirmed their excellent brain permeability with [18F]9 showing better brain heterogeneity and favorable binding kinetics. Pretreatment with different classes of PAMs enhanced the radioactivity uptake for both [18F]8 and [18F]9 at the regions of interest by 20.3-40.9% and 16.7-81.6%, respectively, due to their pharmacological effects. Further evaluation of [18F]9 in a nonhuman primate confirmed its superior brain heterogeneity in mapping mGlu2 receptors and its higher specific binding than [18F]6. Pretreatment with 0.5 mg/kg BINA led (2) to an enhanced brain uptake of [18F]9 by 3% in high tracer uptake regions that was consistent with the rat studies. Therefore, [18F]9 has the potential to be translated for human studies.

neuroscience↗

bioRxiv2021

PET imaging studies to investigate functional expression of mGluR2 using mG2P001

Metabotropic glutamate receptor 2 (mGluR2) has been extensively studied for the treatment of various neurological and psychiatric disorders. Understanding of the mGluR2 function is pivotal in supporting the drug discovery targeting mGluR2. Herein, the positive allosteric modulation of mGluR2 was investigated via the in vivo positron emission tomography (PET) imaging using 2-((4-(2-[11C]methoxy-4-(trifluoromethyl)phenyl)piperidin-1-yl)methyl)-1-methyl-1H-imidazo[4,5-b]pyridine ([11C]mG2P001).Distinct from the orthosteric compounds, pretreatment with the unlabeled mG2P001, a potent mGluR2 positive allosteric modulator (PAM), resulted in a significant increase instead of decrease of the [11C]mG2P001 accumulation in rat brain detected by PET imaging. Subsequent in vitro studies with [3H]mG2P001 revealed the cooperative binding mechanism of mG2P001 with glutamate and its pharmacological effect that contributed to the enhanced binding of [3H]mG2P001 in transfected CHO cells expressing mGluR2. The in vivo PET imaging and quantitative analysis of [11C]mG2P001 in non-human primates (NHPs) further validated the characteristics of [11C]mG2P001 as an imaging ligand for mGluR2. Self-blocking studies in primates enhanced accumulation of [11C]mG2P001 dose- and delivery-dependently. Altogether, these studies show that [11C]mG2P001 is a sensitive biomarker for mGluR2 expression and the binding is affected by the tissue glutamate concentration.

neuroscience↗

bioRxiv2021

Synthesis and characterization of 5-(2-fluoro-4-pyridine-7-carboxamide as a PET imaging ligand for metabotropic glutamate receptor 2

Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for the treatment of several neuropsychiatric disorders and conditions. The role of mGluR2 function in etiology could be unveiled by in vivo imaging using positron emission tomography (PET). In this regard, 5-(2- fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7- carboxamide ([11C]13), a potent negative allosteric modulator (NAM), was developed to support this endeavor. Radioligand [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 {+/-} 76 GBq/{micro}mol (n = 5) and excellent radiochemical purity (> 99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity, particularly in the regions of striatum, thalamus, hippocampus, and cortex. Accumulation of [11C]13 in these regions of interest (ROIs) was reduced with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions, especially in different cortical areas, putamen, thalamus, and hippocampus, and resulted in high-contrast brain images. The regional total volume of distribution (VT) estimates of [11C]13 decreased by 14% after the pretreatment with 9. Therefore, [11C]13 is a potential candidate for translational PET imaging studies of mGluR2 function.

neuroscience↗

bioRxiv2020

Vertical-junction Photodiodes for High-resolution Retinal Prostheses

ObjectiveTo restore central vision in patients with atrophic age-related macular degeneration, we replace the lost photoreceptors with photovoltaic pixels, which convert light into current and stimulate the secondary retinal neurons. Clinical trials demonstrated prosthetic acuity closely matching the sampling limit of the 100 m pixels, and hence smaller pixels are required for improving visual acuity. However, with smaller flat bipolar pixels, the electric field penetration depth and the photodiode responsivity significantly decrease, making the device inefficient. Smaller pixels may be enabled (1) by increasing the diode responsivity using vertical p-n junctions and (2) by directing the electric field vertically using 3-D electrodes. Here, we demonstrate such novel photodiodes and test the retinal stimulation in a vertical electric field. ApproachArrays of silicon photodiodes of 55, 40, 30, and 20 m in width, with vertical p-n junctions, were fabricated. The electric field in the retina was directed vertically by a common return electrode at the edge of the devices. Optical and electronic performance of the diodes was characterized in-vitro, and retinal stimulation threshold measured by recording the visually evoked potentials (VEPs) in rats with retinal degeneration. Main resultsThe photodiodes exhibited sufficiently low dark current (<10 pA) and responsivity at 880 nm wavelength as high as 0.51 A/W, with 85% internal quantum efficiency, independent of pixel size. Field mapping in saline demonstrated uniformity of the pixel performance in the array. The full-field stimulation threshold was as low as 0.057{+/-}0.029 mW/mm2 with 10 ms pulses, independent of pixel size. SignificancePhotodiodes with vertical p-n junctions demonstrated excellent charge collection efficiency independent of pixel size, down to 20 m. Vertically-oriented electric field provides a stimulation threshold that is independent of pixel size. These results are the first steps in validation of the feasibility of scaling down the photovoltaic pixels for subretinal stimulation.

bioengineering↗

bioRxiv2019

Meaningful patterns of information in the brain revealed through analysis of errors

Great excitement has surrounded our ability to decode task information from human brain activity patterns, reinforcing the dominant view of the brain as an information processor. We tested a fundamental but overlooked assumption: that such decodable information is actually used by the brain to generate cognition and behaviour. Participants performed a challenging stimulus-response task during fMRI. Our novel analyses trained a pattern classifier on data from correct trials, and used it to examine stimulus and rule coding on error trials. There was a striking interaction in which frontoparietal cortex systematically represented incorrect rule but correct stimulus information when participants used the wrong rule, and incorrect stimulus but correct rule information on other types of errors. Visual cortex, by contrast, did not code correct or incorrect information on error. Thus behaviour was tightly linked to coding in frontoparietal cortex and only weakly linked to coding in visual cortex. Human behaviour may indeed result from information-like patterns of activity in the brain, but this relationship is stronger in some brain regions than in others. Testing for information coding on error can help establish which patterns constitute behaviourally-meaningful information.

neuroscience↗