Human brain imaging of nicotinic acetylcholine α4β2* receptors using [18F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways

Jogeshwar Mukherjee; Patrick J. Lao; Tobey J. Betthauser; Gurleen K. Samra; Min‐Liang Pan; Ishani H. Patel; Christopher Liang; Raju Metherate; Bradley T. Christian

doi:10.1002/cne.24320

journal article Sep 19, 2017

Human brain imaging of nicotinic acetylcholine α4β2* receptors using [18F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways

Jogeshwar Mukherjee

Patrick J. Lao

Tobey J. Betthauser Gurleen K. Samra Min‐Liang Pan Ishani H. Patel Christopher Liang

Raju Metherate Bradley T. Christian

Journal of Comparative Neurology Vol. 526 No. 1 pp. 80-95 · Wiley

View at Publisher Save 10.1002/cne.24320

Abstract

AbstractNicotinic acetylcholinergic receptors (nAChR's) have been implicated in several brain disorders, including addiction, Parkinson's disease, Alzheimer's disease and schizophrenia. Here we report in vitro selectivity and functional properties, toxicity in rats, in vivo evaluation in humans, and comparison across species of [18F]Nifene, a fast acting PET imaging agent for α4β2* nAChRs. Nifene had subnanomolar affinities for hα2β2 (0.34 nM), hα3β2 (0.80 nM) and hα4β2 (0.83 nM) nAChR but weaker (27–219 nM) for hβ4 nAChR subtypes and 169 nM for hα7 nAChR. In functional assays, Nifene (100 μM) exhibited 14% agonist and >50% antagonist characteristics. In 14‐day acute toxicity in rats, the maximum tolerated dose (MTD) and the no observed adverse effect level (NOAEL) were estimated to exceed 40 μg/kg/day (278 μg/m2/day). In human PET studies, [18F]Nifene (185 MBq; <0.10 μg) was well tolerated with no adverse effects. Distribution volume ratios (DVR) of [18F]Nifene in white matter thalamic radiations were ∼1.6 (anterior) and ∼1.5 (superior longitudinal fasciculus). Habenula known to contain α3β2 nAChR exhibited low levels of [18F]Nifene binding while the red nucleus with α2β2 nAChR had DVR ∼1.6–1.7. Females had higher [18F]Nifene binding in all brain regions, with thalamus showing >15% than males. No significant aging effect was observed in [18F]Nifene binding over 5 decades. In all species (mice, rats, monkeys, and humans) thalamus showed highest [18F]Nifene binding with reference region ratios >2 compared to extrathalamic regions. Our findings suggest that [18F]Nifene PET may be used to study α4β2* nAChRs in various CNS disorders and for translational research.

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Metrics

39

Citations

89

References

Details

Published: Sep 19, 2017
Vol/Issue: 526(1)
Pages: 80-95
License: View

Authors

J

Jogeshwar Mukherjee

Preclinical Imaging, Department of Radiological Sciences University of California Irvine California

P

Patrick J. Lao

Department of Medical Physics and Waisman Center University of Wisconsin Madison Wisconsin

T

Tobey J. Betthauser

Department of Medical Physics and Waisman Center University of Wisconsin Madison Wisconsin

G

Gurleen K. Samra

Preclinical Imaging, Department of Radiological Sciences University of California Irvine California

M

Min‐Liang Pan

Preclinical Imaging, Department of Radiological Sciences University of California Irvine California

I

Ishani H. Patel

Preclinical Imaging, Department of Radiological Sciences University of California Irvine California

C

Christopher Liang

Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697, USA

R

Raju Metherate

Department of Neurobiology and Behavior University of California Irvine California

B

Bradley T. Christian

Department of Medical Physics and Waisman Center University of Wisconsin Madison Wisconsin

Funding

NIH Award: T32 CA009206

National Institute on Aging Award: AG029479

Cite This Article

Jogeshwar Mukherjee, Patrick J. Lao, Tobey J. Betthauser, et al. (2017). Human brain imaging of nicotinic acetylcholine α4β2* receptors using [18F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways. Journal of Comparative Neurology, 526(1), 80-95. https://doi.org/10.1002/cne.24320

Human brain imaging of nicotinic acetylcholine α4β2* receptors using [18F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways

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