A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand

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 OPEN ACCESSMolecules 2015, 20 18388 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

In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors

“…The in vivo distribution of [ 18 F]ASEM found here is very similar to that of [ 11 C]NS14492 and importantly, also in accordance with the distribution of α7 nAChR in the pig brain [31,73]. Furthermore, our data with [ 18 F]ASEM matches previous reports with the structurally similar analogue [ 18 F]DBT-10 in piglets [40].…”

“…While pre-treatment with 1 mg/kg SSR-180,711 resulted in an increased uptake of [ 18 F]ASEM, kinetic modelling for quantification of tracer uptake showed that SSR-180,711 at this dose resulted in 49% occupancy. A similar phenomenon has also been reported in piglets when [ 18 F]DBT-10 was blocked by the weak agonist NS6740, which was ascribed to a potential blood flow-driven effect of NS6740 leading to greater central uptake of [ 18 F]DBT-10 [40]. The increased tracer uptake could also be a result of peripheral α7 nAChR binding sites having been blocked by SSR-180,771.…”

PET imaging of α7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans

“…In contrast to initial in vitro binding results 12 , further in vitro data indicated that [ 18 F]DBT-10 had higher affinity and selectivity for α 7 nAChRs than [ 18 F]ASEM 13 (see Supplement A), motivating our initial characterization of [ 18 F]DBT-10 in nonhuman primates 14 . It is not unusual for a given ligand to exhibit different in vitro binding affinity values under different experimental conditions, particularly for the α 7 nAChR because there is no known conventional in vitro competition binding assay for this receptor.…”

“…Only [ 18 F]ASEM was selected for futher in vivo evaluation because this initial work reported higher in vitro binding affinity and selectivity for [ 18 F]ASEM than [ 18 F]DBT-10 12 (see Supplement A). Subsequent evaluation under different in vitro binding conditions reported that [ 18 F]DBT-10 had higher affinity and selectivity than [ 18 F]ASEM for α 7 nAChRs with similar feasibility for radiofluorination at this position (see Supplement A), thus motivating its preclinical evaluation in PET imaging studies 13 . [ 18 F]DBT-10 was found to have high uptake and binding potentials in nonhuman primates with suitable kinetic properties for in vivo quantification of α 7 nAChR availability 14 .…”

Nurr1, Pitx3, and α7 nAChRs mRNA Expression in Nigral Tissue of Rats with Pedunculopontine Neurotoxic Lesion

“…In relation to the study of the expression of the α7 nAChRs, the finding of the decrease of this variable in rat nigral tissue very early after PPN injury represents an interesting result. Modifications in the functional availability of α7 nAChRs are reported in different neurodegenerative diseases [49]. The majority of the studies on nicotinic neural receptors address aspects related to the activation or desensitization of these in response to lower or higher concentrations of acetylcholine (ACh) or other agonists administered in pharmacological manipulation studies [50,51].…”