Abstract
Changes in the expression of α7 nicotinic acetylcholine receptors (α7 nAChRs) in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled ligands applicable in positron emission tomography (PET). We report on a series of new ligands for α7 nAChRs designed by the combination of dibenzothiophene dioxide as a novel hydrogen bond acceptor functionality with diazabicyclononane as an established cationic center. To assess the structure-activity relationship (SAR) of this new basic structure, we further modified the cationic center systematically by introduction of three different piperazine-based scaffolds. Based on in vitro binding affinity and selectivity, assessed by radioligand displacement studies at different rat and human nAChR subtypes and at the structurally related human 5-HT3 receptor, we selected the compound 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo-[b,d]thiophene 5,5-dioxide (10a) for radiolabeling and further evaluation in vivo. Radiosynthesis of [18F]10a was optimized and transferred to an automated module. Dynamic PET imaging studies with [18F]10a in piglets and a monkey demonstrated high uptake of radioactivity in the brain, followed by washout and target-region specific accumulation under baseline conditions. Kinetic analysis of [18F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [18F]10a ([18F]DBT-10) has high potential to provide clinically relevant information about the expression and availability of α7 nAChR in the brain.
Highlights
The long-standing interest in molecular imaging of nicotinic acetylcholine receptors is driven by findings from preclinical and clinical studies, which have demonstrated that dysfunction of neuronal nAChRs is involved in the pathophysiology of many disorders [1]
Gao et al [17], we have synthesized a series of derivatives of this lead structure to further analyze structural elements that determine the affinity of potential α7 nAChR ligands to other pentameric ligand-gated ion channels such as heteromeric nicotinic or 5-HT3 receptors
To gain further insight into the structure-activity relationship (SAR) of dibenzothiophene-based scaffolds we embarked on the synthesis of a second series of compounds
Summary
Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand. Received: 15 July 2015 / Accepted: 28 September 2015 / Published: 9 October 2015
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