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

Changes in the expression of α₇ nicotinic acetylcholine receptors (α₇ nAChRs) in the human brain are widely assumed to be associated with neurological and neurooncologial 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 combination of dibenzothiophene-dioxide as 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 nAChR subtypes, we selected compound 10a (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo[b,d]thiophene 5,5-dioxide) for radiolabeling and further evaluation in vivo. Radiosynthesis of [¹⁸F]10a was optimized manually and then transferred to an automated module. Dynamic PET imaging studies with [¹⁸F]10a in piglets and a monkey demonstrated robust uptake of radioactivity in the brain, followed by washout and target-region specific accumulation by the radioligand under baseline conditions. Kinetic analysis of [¹⁸F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function and non-displaceable binding potential (BPND) values were estimated in various brain regions. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [¹⁸F]10a has high potential to provide clinically relevant information about the expression and availability of α₇ nAChR in the brain.