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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
- Source :
- 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 2020, ' In vitro and in vivo characterization of dibenzothiophene derivatives [ 125 I]iodo-ASEM and [ 18 F]ASEM as radiotracers of homo-And heteromeric α7 nicotinic acetylcholine receptors ', Molecules, vol. 25, no. 6, 1425 . https://doi.org/10.3390/molecules25061425, Molecules, Vol 25, Iss 6, p 1425 (2020), Molecules, Volume 25, Issue 6
- Publication Year :
- 2020
-
Abstract
- The &alpha<br />7 nicotinic acetylcholine receptor (&alpha<br />7 nAChR) is involved in several cognitive and physiologic processes<br />its expression levels and patterns change in neurologic and psychiatric diseases, such as schizophrenia and Alzheimer&rsquo<br />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]&alpha<br />bungarotoxin, specific binding was absent in &alpha<br />7 nAChR gene-deficient mice and binding was blocked by a range of &alpha<br />7 nAChR orthosteric modulators in an affinity-dependent order in the pig brain. Interestingly, relative to the wild-type, binding in &beta<br />2 nAChR gene-deficient mice was lower for [125I]Iodo-ASEM (58% &plusmn<br />2.7%) than [125I]&alpha<br />bungarotoxin (23% &plusmn<br />0.2%), potentially indicating different binding properties to heteromeric &alpha<br />7&beta<br />2 nAChR. [18F]ASEM PET in the pig showed high brain uptake and reversible tracer kinetics with a similar spatial distribution as previously reported for &alpha<br />7 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 &alpha<br />7 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 &alpha<br />7 nAChR, comparable to previously published data.
- Subjects :
- Alpha 7
Nicotinic acetylcholine receptors
Pharmaceutical Science
autoradiography
Analytical Chemistry
lcsh:QD241-441
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
α7 nicotinic acetylcholine receptor
pet
lcsh:Organic chemistry
In vivo
Drug Discovery
nachr
Physical and Theoretical Chemistry
Receptor
030304 developmental biology
Brain uptake
0303 health sciences
Chemistry
Organic Chemistry
Binding properties
NAChR
In vitro
PET
Chemistry (miscellaneous)
Dibenzothiophene
Biophysics
Molecular Medicine
alpha 7
Autoradiography
nicotinic acetylcholine receptors
α7 nachr
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- 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 2020, ' In vitro and in vivo characterization of dibenzothiophene derivatives [ 125 I]iodo-ASEM and [ 18 F]ASEM as radiotracers of homo-And heteromeric α7 nicotinic acetylcholine receptors ', Molecules, vol. 25, no. 6, 1425 . https://doi.org/10.3390/molecules25061425, Molecules, Vol 25, Iss 6, p 1425 (2020), Molecules, Volume 25, Issue 6
- Accession number :
- edsair.doi.dedup.....5d7a4f4c38269985293d3d205a568c10
- Full Text :
- https://doi.org/10.3390/molecules25061425