Brain PET Imaging of α7-nAChR with [18F]ASEM: Reproducibility, Occupancy, Receptor Density, and Changes in Schizophrenia

Wong, Dean F.; Kuwabara, Hiroto; Horti, Andrew G.; Roberts, Janet Hatcher; Nandi, Ayon; Cascella, Nicola G.; Brašić, James Robert; Weerts, Elise M.; Kitzmiller, Kelly; Phan, Jenny-Ann; Gapasin, Lorena; Sawa, Akira; Valentine, Heather; Wand, Gary S.; Mishra, Chakradhar; George, Noble; McDonald, Michael; Lesniak, Wojtek; Holt, Daniel P.; Azad, Babak Behnam; Dannals, Robert F.; Kem, William R.; Freedman, Robert; Gjedde, Albert

doi:10.1093/ijnp/pyy021

Cited by 47 publications

(31 citation statements)

References 65 publications

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“…These findings are consistent with previous in vivo microdialysis studies showing activation of a7 nAChR is associated with increased neurotransmitter release in various brain regions, including prefrontal cortex (Biton et al, 2007;Tietje et al, 2008;Livingstone et al, 2009). Over the last decade, significant progress has been made toward developing novel a7 positron emission tomography tracers that bind to the orthosteric binding site (Chalon et al, 2015), such as [18F]ASEM, which has advanced to clinic to determine the target engagement of a7 agonists (Wong et al, 2014(Wong et al, , 2018. However, developing an a7 positron emission tomography tracer targeting the allosteric binding site has been a challenge.…”

Section: Discussionsupporting

confidence: 88%

Pharmacological Characterization of the Novel and Selective α7 Nicotinic Acetylcholine Receptor–Positive Allosteric Modulator BNC375

Wang

Daley

Gakhar

et al. 2020

J Pharmacol Exp Ther

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Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The a7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with a7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective a7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked a7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13 C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that a7 nAChR PAMs have multiple advantages over orthosteric a7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENTBNC375 is a novel and selective a7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked a7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that a7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.This work was funded by Merck & Co., Inc. and Bionomics Limited.

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Section: Discussionsupporting

confidence: 88%

Pharmacological Characterization of the Novel and Selective α7 Nicotinic Acetylcholine Receptor–Positive Allosteric Modulator BNC375

Wang

Daley

Gakhar

et al. 2020

J Pharmacol Exp Ther

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“…α 7-nAChR mediates various brain functions and represents an important target for drug discovery. In clinical trials with selective α 7 agonists, activation of the receptor improved cognitive performance in patients with schizophrenia [ 84 ]. The recently developed 18 F-ASEM, a highly α 7-nAChR specific and selective radiotracer for brain PET, opens new horizons for studying α 7-nAChRs in the living human brain.…”

Section: Discussionmentioning

confidence: 99%

The Place of PET to Assess New Therapeutic Effectiveness in Neurodegenerative Diseases

Dupont

Largeau

Guilloteau

et al. 2018

Contrast Media & Molecular Imaging

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In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging has matured over the last 20 years, using dedicated radiopharmaceuticals targeting cellular metabolism, neurotransmission, neuroinflammation, or abnormal protein aggregates (beta-amyloid and intracellular microtubule inclusions containing hyperphosphorylated tau). The ability of PET to characterize biological processes at the cellular and molecular levels enables early detection and identification of molecular mechanisms associated with disease progression, by providing accurate, reliable, and longitudinally reproducible quantitative biomarkers. Thus, PET imaging has become a relevant imaging method for monitoring response to therapy, approved as an outcome measure in bioclinical trials. The aim of this paper is to review and discuss the current inputs of PET in the assessment of therapeutic effectiveness in neurodegenerative diseases connected by common pathophysiological mechanisms, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. We also discuss opportunities for PET imaging to drive more personalized neuroprotective and therapeutic strategies, taking into account individual variability, within the growing framework of precision medicine.

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“…18 F-FEOBV was shown to have the highest sensitivity compared with both 18 F-FDG (metabolism) and 18 F-NAV4694 (amyloid) for distinguishing between HC and AD patients in a smallscale study [67]. 18 F-ASEM V T was found to be significantly decreased in schizophrenia patients in some brain regions, although an outlier was excluded in order to achieve this [75]. Additionally, an occupancy of up to 49% was determined when schizophrenic patients were treated with α7-nAChR selective agonist DXMB-A.…”

Section: Conclusion and Outstanding Issues For Recent Cholinergic Trmentioning

confidence: 97%

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

McCluskey

Plisson

Rabiner

et al. 2019

Eur J Nucl Med Mol Imaging

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Purpose A limit on developing new treatments for a number of central nervous system (CNS) disorders has been the inadequate understanding of the in vivo pathophysiology underlying neurological and psychiatric disorders and the lack of in vivo tools to determine brain penetrance, target engagement, and relevant molecular activity of novel drugs. Molecular neuroimaging provides the tools to address this. This article aims to provide a state-of-the-art review of new PET tracers for CNS targets, focusing on developments in the last 5 years for targets recently available for inhuman imaging. Methods We provide an overview of the criteria used to evaluate PET tracers. We then used the National Institute of Mental Health Research Priorities list to identify the key CNS targets. We conducted a PubMed search (search period 1st of January 2013 to 31st of December 2018), which yielded 40 new PET tracers across 16 CNS targets which met our selectivity criteria. For each tracer, we summarised the evidence of its properties and potential for use in studies of CNS pathophysiology and drug evaluation, including its target selectivity and affinity, inter and intra-subject variability, and pharmacokinetic parameters. We also consider its potential limitations and missing characterisation data, but not specific applications in drug development. Where multiple tracers were present for a target, we provide a comparison of their properties. Results and conclusions Our review shows that multiple new tracers have been developed for proteinopathy targets, particularly tau, as well as the purinoceptor P2X7, phosphodiesterase enzyme PDE10A, and synaptic vesicle glycoprotein 2A (SV2A), amongst others. Some of the most promising of these include 18 F-MK-6240 for tau imaging, 11 C-UCB-J for imaging SV2A, 11 C-CURB and 11 C-MK-3168 for characterisation of fatty acid amide hydrolase, 18 F-FIMX for metabotropic glutamate receptor 1, and 18 F-MNI-444 for imaging adenosine 2A. Our review also identifies recurrent issues within the field. Many of the tracers discussed lack in vivo blocking data, reducing confidence in selectivity. Additionally, late-stage identification of substantial off-target sites for multiple tracers highlights incomplete preclinical characterisation prior to translation, as well as human disease state studies carried out without confirmation of test-retest reproducibility.

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Brain PET Imaging of α7-nAChR with [18F]ASEM: Reproducibility, Occupancy, Receptor Density, and Changes in Schizophrenia

Cited by 47 publications

References 65 publications

Pharmacological Characterization of the Novel and Selective α7 Nicotinic Acetylcholine Receptor–Positive Allosteric Modulator BNC375

Pharmacological Characterization of the Novel and Selective α7 Nicotinic Acetylcholine Receptor–Positive Allosteric Modulator BNC375

The Place of PET to Assess New Therapeutic Effectiveness in Neurodegenerative Diseases

Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development

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