Development of ¹¹C-Labeled ASEM Analogues for the Detection of Neuronal Nicotinic Acetylcholine Receptors (α7-nAChR)

Abstract

The homo-pentameric alpha 7 receptor is one of the major types of neuronal nicotinic acetylcholine receptors (α7-nAChRs) related to cognition, memory formation, and attention processing. The mapping of α7-nAChRs by PET pulls a lot of attention to realize the mechanism and development of CNS diseases such as AD, PD, and schizophrenia. Several PET radioligands have been explored for the detection of the α7-nAChR. 18 F-ASEM is the most functional for in vivo quantification of α7-nAChRs in the human brain. The first aim of this study was to initially use results from in silico and machine learning techniques to prescreen and predict the binding energy and other properties of ASEM analogues and to interpret these properties in terms of atomic structures using 18 F-ASEM as a lead structure, and second, to label some selected candidates with carbon-11/hydrogen-3 ( 11 C/ 3 H) and to evaluate the binding properties in vitro and in vivo using the labeled candidates. In silico predictions are obtained from perturbation free-energy calculations preceded by molecular docking, molecular dynamics, and metadynamics simulations. Machine learning techniques have been applied for the BBB and P-gp-binding properties. Six analogues of ASEM were labeled with 11 C, and three of them were additionally labeled with 3 H. Binding properties were further evaluated using autoradiography (ARG) and PET measurements in non-human primates (NHPs). Radiometabolites were measured in NHP plasma. All six compounds were successfully synthesized. Evaluation with ARG showed that 11 C-Kln83 was preferably binding to the α7-nAChR. Competition studies showed that 80% of the total binding was displaced. Further ARG studies using 3 H-KIn-83 replicated the preliminary results. In the NHP PET study, the distribution pattern of 11 C-KIn-83 was similar to other α7 nAChR PET tracers. The brain uptake was relatively low and increased by the administration of tariquidar, indicating a substrate of P-gp. The ASEM blocking study showed that 11 C-KIn-83 specifically binds to α7 nAChRs. Preliminary in vitro evaluation of KIn-83 by ARG with both 11 C and 3 H and in vivo evaluation in NHP showed favorable properties for selectively imaging α7-nAChRs, despite a relatively low brain uptake.

Diagnostic and Therapeutic Radiopharmaceuticals

“…Novel chelators have been reported to be able to incorporate, with high yields, radiometals such as [ 203 Pb]­Pb 2+ , [ 213 Bi]­Bi 3+ , [ 225 Ac]­Ac 3+ , and [ 90 Y]­Y 3+ in short reaction times and under mild conditions with a broad range of pH values. − Metal–ligand complexes have been confirmed by 1 H NMR spectroscopy, X-ray crystallography, potentiometry, and computational studies. − Development of novel radiotracers to image central nervous system (CNS) receptors. Radiopharmaceuticals binding opioid σ2 receptors, purinergic P2Y 12 receptors, sphingosine-1-phosphate receptor 1, α7 nicotinic acetylcholine receptors, cannabinoid receptor type 2, and Aβ oligomers and plaques have been studied in rodents and non-human primates, demonstrating their ability to cross the blood–brain barrier and bind to CNS targets. Ligand–target interactions at the atomic level have been predicted by perturbation free-energy calculations, molecular docking, molecular dynamics, and metadynamics simulations. ,, Development of radioligands for cancer imaging and therapy with prolonged half-life in vivo and high tumor-to-background contrast.…”

“…Radiopharmaceuticals binding opioid σ2 receptors, purinergic P2Y 12 receptors, sphingosine-1-phosphate receptor 1, α7 nicotinic acetylcholine receptors, cannabinoid receptor type 2, and Aβ oligomers and plaques have been studied in rodents and non-human primates, demonstrating their ability to cross the blood–brain barrier and bind to CNS targets. Ligand–target interactions at the atomic level have been predicted by perturbation free-energy calculations, molecular docking, molecular dynamics, and metadynamics simulations. ,, Development of radioligands for cancer imaging and therapy with prolonged half-life in vivo and high tumor-to-background contrast. To reach this aim, the addition of albumin-binding and immunoglobulin-binding domains in FAP- and PSMA-targeting radioligands , and HER2 nanobodies has been chosen to prolong their blood circulation time, enhance tumor uptake, and prolong tumor residence .…”

“…Ligand−target interactions at the atomic level have been predicted by perturbation free-energy calculations, molecular docking, molecular dynamics, and metadynamics simulations. 24,26,28…”

“…Development of novel radiotracers to image central nervous system (CNS) receptors. Radiopharmaceuticals binding opioid σ2 receptors, purinergic P2Y 12 receptors, sphingosine-1-phosphate receptor 1, α7 nicotinic acetylcholine receptors, cannabinoid receptor type 2, and Aβ oligomers and plaques have been studied in rodents and non-human primates, demonstrating their ability to cross the blood–brain barrier and bind to CNS targets. Ligand–target interactions at the atomic level have been predicted by perturbation free-energy calculations, molecular docking, molecular dynamics, and metadynamics simulations. ,, …”

“…Development of novel radiochemical reactions or chelators to incorporate diagnostic and therapeutic radionuclides in their chemical structure. 10−14 Papers describing novel methods for radiocyanation of aryl halides for the introduction of [ 11 C]CN into peptides, 15 18 F-trifluoromethylation of unmodified peptides at tryptophan and tyrosine residues, 16 and formation of [ 22 sphingosine-1-phosphate receptor 1, 23 α7 nicotinic acetylcholine receptors, 24 cannabinoid receptor type 2, 25 and Aβ oligomers 26 and plaques 27 have been studied in rodents and non-human primates, demonstrating their ability to cross the blood−brain barrier and bind to CNS targets. Ligand−target interactions at the atomic level have been predicted by perturbation free-energy calculations, molecular docking, molecular dynamics, and metadynamics simulations.…”