Development of [ 18 F]ASEM, a specific radiotracer for quantification of the α7-nAChR with positron-emission tomography

Abstract

The alpha-7 subtype of the nicotinic acetylcholine receptor (α7-nAChR) is fundamental to physiology; it mediates various brain functions and represents an important target for drug discovery. Exploration of the brain nicotinic acetylcholine receptors (nAChRs) using positron-emission tomography (PET) will make it possible to better understand the important role of this receptor and to study its involvement in schizophrenia, bipolar disorder, Alzheimer's and Parkinson's diseases, drug dependence, inflammation and many other disorders and simplify the development of nicotinic drugs for treatment of these disorders. Until recently, PET imaging of α7-nAChRs has been impeded by the absence of good radiotracers. This review describes various endeavors to develop α7-nAChR PET tracers by several research groups including the author’s group. Most initial PET tracers for imaging α7-nAChRs did not exhibit suitable imaging properties due to their low specific binding. Recently discovered [18F]ASEM is the first highly specific α7-nAChR radioligand and it was recently translated to human PET imaging.

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

“…A dose of 0.33 mg/kg varenicline, estimated as roughly twice the therapeutic dose 38 , resulted in no significant effects on [ 18 F]ASEM V T . While varenicline has an order of magnitude higher affinity for α 7 nAChRs than nicotine 16 , its affinity is still roughly three orders of magnitude lower than that of ASEM 9 , and therapeutic doses of varenicline are not expected to induce functional effects on α 7 nAChRs 38 . Thus the data suggesting no competition of 0.33 mg/kg varenicline with [ 18 F]ASEM is not unexpected.…”

“…However, it displayed poor specificity for α 7 nAChRs and high nonspecific uptake, resulting in low specific binding signal 8 . The second α 7 nAChR PET radioligand was [ 18 F]ASEM, which exhibited high binding potentials, dose-dependent response to α 7 nAChR blockade, and appropriate kinetic properties for imaging human subjects 9–11 . As part of the initial development of [ 18 F]ASEM, the Johns Hopkins group synthesized another α 7 nAChR compound based on the same dibenzothiophene scaffold, (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([ 18 F]fluorodibenzo[ b,d ]thiophene 5,5-dioxide), initially referred to as either [ 18 F] para -ASEM or [ 18 F]JHU82108 9 , and referred to elsewhere and here as [ 18 F]DBT-10 (see Figure 1).…”

“…The second α 7 nAChR PET radioligand was [ 18 F]ASEM, which exhibited high binding potentials, dose-dependent response to α 7 nAChR blockade, and appropriate kinetic properties for imaging human subjects 9–11 . As part of the initial development of [ 18 F]ASEM, the Johns Hopkins group synthesized another α 7 nAChR compound based on the same dibenzothiophene scaffold, (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([ 18 F]fluorodibenzo[ b,d ]thiophene 5,5-dioxide), initially referred to as either [ 18 F] para -ASEM or [ 18 F]JHU82108 9 , and referred to elsewhere and here as [ 18 F]DBT-10 (see Figure 1). 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).…”

PET Brain imaging of α7-nAChR with [18F]ASEM

“…Many radiotracers of interest to α7-nAChR ( 11 C-CHIBA-1001 (Toyohara et al, 2009), 11 C-NS14492 (Ettrup et al, 2011;Magnussen et al, 2015) and others) have been tested, but most had suboptimal properties in PET of humans (see Gao et al (2013) for review). Here, we further tested human subjects with [ 18 F]ASEM, the only α7-nAChR PET tracer available to humans with promising imaging characteristics (Gao et al, 2013b;Horti et al, 2014b;Horti, 2015;Coughlin et al, 2017;Hillmer et al, 2017;Wong et al, 2017). Objectives included 1) confirmation of test-retest reproducibility of [ 18 F]ASEM binding in brain of normal volunteers, 2) demonstration for the first time of specific binding and target engagement/occupancy in human brain of the partial agonist DMXB-A (GTS-21), 3) estimation for the first time of [ 18 F]ASEM binding potentials and α7-nAChR receptor density (B max ) and inhibitor affinity constant (K I ) for human brain in vivo, and 4) preliminary evaluation of the target role of α7-nAChR in psychosis in six patients with schizophrenia.…”

Molecular Imaging of the Nicotinic Cholinergic Receptor in Alzheimer Disease

“…These issues are being addressed through recent developments in radiotracer chemistry and progress in being made on the development of α7 subtype radiotracers as well. 5,6 Importantly, major insights into the role of the nicotinic system in aging have been made by combining pharmacological manipulations of the nicotinic system with task-based functional magnetic resonance imaging studies. 7 …”