- Enhanced arecoline derivatives as muscarinic acetylcholine receptor M1 ligands for potential application as PET radiotracers
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Supported by their involvement in many neurodegenerative disorders, muscarinic acetylcholine receptors (mAChRs) are an interesting target for PET imaging. Nevertheless, no radiotracer is established in clinical routine. Within this work we aim to develop novel PET tracers based on the structure of arecoline. Fifteen novel arecoline derivatives were synthesized, characterized and tested for their affinity to the mAChRs M1-M5 and the conceivable off-target acetylcholinesterase. Five arecoline derivatives and arecoline were labeled with carbon-11 in good yields. Arecaidine diphenylmethyl ester (3b), arecaidine bis(4-fluorophenyl)methyl ester (3c) and arecaidine (4-bromophenyl)(4-fluorophenyl)methyl ester (3e) showed a tremendous gain in mAChR affinity compared to arecoline and a pronounced subtype selectivity for M1. Metabolic stability and serum protein binding of [11C]3b and [11C]3c were in line with properties of established brain tracers. Nonspecific binding of [11C]3c was prevalent in kinetic and endpoint experiment on living cells as well as in autoradiography on native mouse brain sections, which motivates us to decrease the lipophilicity of this substance class prior to in vivo experiments.
- Ozenil, Marius,Pacher, Katharina,Balber, Theresa,Vraka, Chrysoula,Roller, Alexander,Holzer, Wolfgang,Spreitzer, Helmut,Mitterhauser, Markus,Wadsak, Wolfgang,Hacker, Marcus,Pichler, Verena
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supporting information
(2020/07/27)
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- Unexpected Formation of a 11H-Pyridoquinazolin-11-one Derivative from 5,11-Dihydro-6H-pyrido-1,4-benzodiazepin-6-one
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The unexpected formation of 11H-pyridoquinazolin-11-one derivative 6 from 5,11-dihydro-6H-pyrido-1,4-benzodiazepin-6-one (2) has been observed.Its structure 6 was determined by X-ray crystallography.Detailed nmr study provided a complete set of proton and carbon-13 nmr parameters of compound 6 in solution.
- Budesinsky, Milos,Symersky, Jindrich,Podlaha, Jaroslav,Podlahova, Jana,Polivka, Zdenek,Protiva, Miroslav
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p. 1229 - 1235
(2007/10/02)
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- EXPERIMENTAL ANTIULCER AGENTS: N-SUBSTITUTED 2-(4-METHYL-1-PIPERAZINYL)ACETAMIDES AS PIRENZEPINE MODELS AND SOME RELATED COMPOUNDS
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Reactions of N-cyclohexyl-2-chloroacetamide, N-phenyl-2-chloroacetamide, N-(4-dimethylaminophenyl)-2-chloroacetamide, N-(2-nitrophenyl)-N-phenyl-2-chloroacetamide, its 3-nitrophenyl and 4-nitrophenyl analogues, N-(2-benzylphenyl)-2-chloroacetamide, 5-(chloroacetyl)dibenzazepine, and its 10,11-dihydro derivative with piperazine, 1-methylpiperazine, 2-(1-piperazinyl)ethanol, and 3-(1-piperazinyl)propanol resulted in compounds II, III, V -XV, XVIII, XXI, and XXIII, simple analogues of the antiulcer agent pirenzepine (I).Contributions to the syntheses and characterization of mianserin (XIX), bisnor analogue of imipramine (XXV), and pirenzepine (I) are presented.Two 2-aryl-2-(2-pyridyl)thioacetamides XXXVIII and XL were synthesized via nitriles XXXIX and XLI.Compounds XI (VUFB-17 104) and XXI (VUFB-17 113) were found to be rather effective as anti-ulcer agents and anticholinergics.
- Hulinska, Hana,Polivka, Zdenek,Jilek, Jiri,Sindelar, Karel,Holubek, Jiri,et al.
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p. 1820 - 1844
(2007/10/02)
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- New Synthesis of 11-Acyl-5,11-dihydro-6H-pyridobenzodiazepin-6-ones and Related Studies
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New synthesis of 11-acyl-5,11-dihydro-6H-pyridobenzodiazepin-6-ones (42-44) is reported.The crucial steps (Scheme VI) represented N-oxidation of 1 (1A) to 35 (35A), facilitated ring-closure of 36 into 37, its subsequent N-α-chloroacetylation to 38, aminolysis to 39-41 (involving N-O anchimeric assistance as depicted in 38A) and deoxygenation to 42-44 (Scheme VII).The central intermediate 37 is also obtained on oxygenation of 2, a new synthesis of which was reported in the previous paper of this series .Other attempts of cyclisation "from the top" or "from the bottom" (Scheme I) are described.Thus, interaction of 1 with acetamide afforded 3 and 4 instead of the expected 2A.Compound 5 cyclised into 3-pyridoquinazolone 6 while its 2-(4'-methylpiperazin-1'-yl) analogue 9 was observed to be unstable for the attempted ring-opening and reclosure to 42. "From the bottom" cyclisations of 10A-10C, via intermediary amines 11A-11C failed and pyridoquinazolinone 13 was isolated (Scheme V).The attempted oxidative cyclisation of the compounds 15 and 18 into 2 and 42, respectively, 13 afforded imidazolopyridine derivative (18-19), while 15 remained unchanged. 3-Acylamino-2-arylaminopyridines (21-24), cyclised into the imidazolopyridines 29-30.Model compounds 45-50 were prepared to study selective aminolysis of the chlorine atoms in 2-chloro-3-(2'-chlorobenzoyl)aminopyridine 1, and its N-oxide 35.
- Kovac, T.,Oklobdzija, M.,Comisso, G.,Decorte, E.,Fajdiga, T.,et al.
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p. 1339 - 1349
(2007/10/02)
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