Next Article in Journal
Recent Advances in Berberine Inspired Anticancer Approaches: From Drug Combination to Novel Formulation Technology and Derivatization
Next Article in Special Issue
Current Landscape and Emerging Fields of PET Imaging in Patients with Brain Tumors
Previous Article in Journal
Synthetic Studies to Help Elucidate the Metabolism of the Preclinical Candidate TBAJ-876—A Less Toxic and More Potent Analogue of Bedaquiline
Previous Article in Special Issue
A New Positron Emission Tomography Probe for Orexin Receptors Neuroimaging
Open AccessArticle

In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors

Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark
Department of Brain Sciences, Imperial College London, London W12 0 LS, UK
Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, 2100 Copenhagen, Denmark
Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark
DanPET AB, 216 19 Malmö, Sweden
Authors to whom correspondence should be addressed.
Academic Editor: Peter Brust
Molecules 2020, 25(6), 1425;
Received: 24 January 2020 / Revised: 25 February 2020 / Accepted: 27 February 2020 / Published: 20 March 2020
(This article belongs to the Special Issue Radiolabelled Molecules for Brain Imaging with PET and SPECT)
The α7 nicotinic acetylcholine receptor (α7 nAChR) is involved in several cognitive and physiologic processes; its expression levels and patterns change in neurologic and psychiatric diseases, such as schizophrenia and Alzheimer’s disease, which makes it a relevant drug target. Development of selective radioligands is important for defining binding properties and occupancy of novel molecules targeting the receptor. We tested the in vitro binding properties of [125I]Iodo-ASEM [(3-(1,4-diazabycyclo[3.2.2]nonan-4-yl)-6-(125I-iododibenzo[b,d]thiopentene 5,5-dioxide)] in the mouse, rat and pig brain using autoradiography. The in vivo binding properties of [18F]ASEM were investigated using positron emission tomography (PET) in the pig brain. [125I]Iodo-ASEM showed specific and displaceable high affinity (~1 nM) binding in mouse, rat, and pig brain. Binding pattern overlapped with [125I]α-bungarotoxin, specific binding was absent in α7 nAChR gene-deficient mice and binding was blocked by a range of α7 nAChR orthosteric modulators in an affinity-dependent order in the pig brain. Interestingly, relative to the wild-type, binding in β2 nAChR gene-deficient mice was lower for [125I]Iodo-ASEM (58% ± 2.7%) than [125I]α-bungarotoxin (23% ± 0.2%), potentially indicating different binding properties to heteromeric α7β2 nAChR. [18F]ASEM PET in the pig showed high brain uptake and reversible tracer kinetics with a similar spatial distribution as previously reported for α7 nAChR. Blocking with SSR-180,711 resulted in a significant decrease in [18F]ASEM binding. Our findings indicate that [125I]Iodo-ASEM allows sensitive and selective imaging of α7 nAChR in vitro, with better signal-to-noise ratio than previous tracers. Preliminary data of [18F]ASEM in the pig brain demonstrated principal suitable kinetic properties for in vivo quantification of α7 nAChR, comparable to previously published data. View Full-Text
Keywords: alpha 7; nicotinic acetylcholine receptors; PET; nAChR; autoradiography alpha 7; nicotinic acetylcholine receptors; PET; nAChR; autoradiography
Show Figures

Graphical abstract

MDPI and ACS Style

Donat, C.K.; Hansen, H.H.; Hansen, H.D.; Mease, R.C.; Horti, A.G.; Pomper, M.G.; L’Estrade, E.T.; Herth, M.M.; Peters, D.; Knudsen, G.M.; Mikkelsen, J.D. In Vitro and In Vivo Characterization of Dibenzothiophene Derivatives [125I]Iodo-ASEM and [18F]ASEM as Radiotracers of Homo- and Heteromeric α7 Nicotinic Acetylcholine Receptors. Molecules 2020, 25, 1425.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Back to TopTop