Recent PET radioligands with optimal brain kinetics for imaging nicotinic acetylcholine receptors

Horti, Andrew G.; Kuwabara, Hiroto; Holt, Daniel P.; Dannals, Robert F.; Wong, Dean F.

doi:10.1002/jlcr.3020

Cited by 24 publications

(22 citation statements)

References 54 publications

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“…Several limitations may be considered in our study. Firstly, the major intrinsic limitation of the tracer F-A-85380 is its slow brain kinetics and the long time after injection required in humans to reach equilibrium (Mamede, Ishizu et al 2004, Horti, Kuwabara et al 2013. We adopted a static late imaging protocol, without arterial sampling, as previously validated (Picard, Bruel et al 2006) and used in other clinical studies, e.g.…”

Section: Methodological Limitations Of the Studymentioning

confidence: 99%

Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy

Garibotto

Wissmeyer²,

Giavri³

et al. 2018

Eur J Nucl Med Mol Imaging

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Mutations of cholinergic neuronal nicotinic receptors have been identified in the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), associated with changes on PET images using [ 18 F]-F-85380-A (F-A-85380), an α4β2 nicotinic receptor ligand. The aim of the present study was to evaluate potential changes in nicotinic receptor availability in other types of epilepsy. Methods: We included 34 male participants, 12 patients with idiopathic generalized epilepsy (IGE), 10 with non lesional diurnal focal epilepsy, and 12 age-matched healthy controls. All patients underwent PET/CT using F-A-85380 and [ 18 F]-fluorodeoxyglucose (FDG), 3D T1 MRI and diffusion tensor imaging (DTI). F-A-85380 and FDG images were compared with the control group using a voxel-wise (SPM12) and a volumes of interest (VOI) analysis. Results: In the group of patients with IGE, the voxel-wise and VOI analyses showed a significant increase of F-A-85380 ratio index of binding potential (BPRI, corresponding to the receptor availability) in the anterior cingulate cortex (ACC), without structural changes on MRI. At an individual level, F-A-85380 BPRI increase in the ACC could distinguish IGE patients from controls and from patients with focal epilepsy with good accuracy. Conclusions: We observed focal changes of density/availability of nicotinic receptors in IGE, namely an increase in the ACC. These data suggest that the modulation of α4β2 nicotinic receptors plays a role not only in ADNFLE but also in other genetic epileptic syndromes such as IGE and could serve as a biomarker of epilepsy syndromes with a genetic background.

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Section: Methodological Limitations Of the Studymentioning

confidence: 99%

Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy

Garibotto

Wissmeyer²,

Giavri³

et al. 2018

Eur J Nucl Med Mol Imaging

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“…AD is associated with failure of cholinergic neurotransmission, but its relation to clinical symptoms and disease progression is still poorly understood. Thus, ongoing research into development of suitable PET tracers (131) may allow future studies on the relation between pathological protein deposition and their functional interactions and consequences.…”

Section: Molecular Imaging Markers: Pet Fdg Amyloid Tau Neuroinflamentioning

confidence: 99%

The Road Ahead to Cure Alzheimer\'s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across All Stages and Target Populations

Cavedo¹,

Lista²,

Khachaturian³

et al. 2014

J Prev Alz Dis

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Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1- 40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for “prodromal AD” and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.

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“…In diseases of the central nervous system, two nAChRs, (α 4 ) 2 (β 2 ) 3 and (α 7 ) 5 , have emerged as key targets for both therapeutic agents and PET radiotracers. Several radiotracers have emerged for selective imaging of each of these two nAChRs including [ 11 C]‐CHIBA‐1001, [ 11 C]‐NS14492, and [ 18 F]‐NS10743 amongst others for imaging (α 7 ) 5 receptors, and 2‐[ 18 F]‐FA, 6‐[ 18 F]‐FA, [ 18 F]‐nifene, [ 18 F]‐AZAN, and 2‐[ 18 F]‐A85380 for binding to the β 2 subunit of (α4) 2 (β 2 ) 3 receptors.…”

Section: Alternative Targets For Positron Emission Tomography Imagingmentioning

confidence: 99%

Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque

Holland

Liang

Rotstein

et al. 2013

Labelled Comp Radiopharmac

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Alzheimer's disease (AD) and related dementias show increasing clinical prevalence, yet our understanding of the etiology and pathobiology of disease-related neurodegeneration remains limited. In this regard, noninvasive imaging with radiotracers for positron emission tomography (PET) presents a unique tool for quantifying spatial and temporal changes in characteristic biological markers of brain disease and for assessing potential drug efficacy. PET radiotracers targeting different protein markers are being developed to address questions pertaining to the molecular and/or genetic heterogeneity of AD and related dementias. For example, radiotracers including [(11) C]-PiB and [(18) F]-AV-45 (Florbetapir) are being used to measure the density of Aβ-plaques in AD patients and to interrogate the biological mechanisms of disease initiation and progression. Our focus is on the development of novel PET imaging agents, targeting proteins beyond Aβ-plaques, which can be used to investigate the broader mechanism of AD pathogenesis. Here, we present the chemical basis of various radiotracers which show promise in preclinical or clinical studies for use in evaluating the phenotypic or biochemical characteristics of AD. Radiotracers for PET imaging neuroinflammation, metal ion association with Aβ-plaques, tau protein, cholinergic and cannabinoid receptors, and enzymes including glycogen-synthase kinase-3β and monoamine oxidase B amongst others, and their connection to AD are highlighted.

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Recent PET radioligands with optimal brain kinetics for imaging nicotinic acetylcholine receptors

Cited by 24 publications

References 54 publications

Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy

Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy

The Road Ahead to Cure Alzheimer\'s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across All Stages and Target Populations

Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque

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