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Synthesis and preliminary evaluation of 18F-labeled 1-(6,7-dimethyl-4-(methylamino)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-(trans-2-(6-fluoropyridin-3-yl)cyclopropyl)ethan-1-one for imaging muscarinic acetylcholine receptor subtype 4
Synthesis and preliminary evaluation of 18F-labeled 1-(6,7-dimethyl-4-(methylamino)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2-(trans-2-(6-fluoropyridin-3-yl)cyclopropyl)ethan-1-one for imaging muscarinic acetylcholine receptor subtype 4
- Source :
- Tetrahedron Letters. 61:152060
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Positive allosteric modulators of muscarinic acetylcholine receptor subtype 4 have been identified as promising activators for the treatment of neurological disorders and neurodegenerative diseases, including schizophrenia, Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Herein we report the synthesis and preliminary evaluation of a 18F-labeled positron emission tomography ligand based on a M4 activator (7). 18F-Isotopologue of 7 was prepared in a reasonable radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed moderate in vitro specific binding. Dynamic PET studies in vivo demonstrated that [18F]7 (also named as [18F]M4R-1911) failed to cross the blood–brain barrier. Therefore, further chemical scaffold optimization in chemotype of 7 is necessary to overcome limited brain permeability and improve specific binding.
- Subjects :
- 010405 organic chemistry
Activator (genetics)
Chemistry
Stereochemistry
Dementia with Lewy bodies
Organic Chemistry
Allosteric regulation
010402 general chemistry
Ligand (biochemistry)
medicine.disease
01 natural sciences
Biochemistry
In vitro
0104 chemical sciences
In vivo
Drug Discovery
Muscarinic acetylcholine receptor
medicine
Subjects
Details
- ISSN :
- 00404039
- Volume :
- 61
- Database :
- OpenAIRE
- Journal :
- Tetrahedron Letters
- Accession number :
- edsair.doi...........37d36b19f58ce4579e959f51c06bccb3
- Full Text :
- https://doi.org/10.1016/j.tetlet.2020.152060