Synthesis and biological evaluation of novel carbon-11-labelled analogues of citalopram as potential radioligands for the serotonin transporter

Three serotonin reuptake inhibitors where the 5-cyano group in citalopram [1-(3-dimethylamino-propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile ( 1)] was replaced with a methyl, acetyl and piperidinyl carbonyl group, respectively, were synthesized. In a Stille reaction applying [ 11...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry Vol. 11; no. 16; pp. 3447 - 3456
Main Authors:	Madsen, Jacob, Merachtsaki, Pinelopi, Davoodpour, Padideh, Bergström, Mats, Långström, Bengt, Andersen, Kim, Thomsen, Christian, Martiny, Lars, Knudsen, Gitte M
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 05-08-2003 Elsevier Science
Subjects:	Acetylation Alkaloids - chemical synthesis Alkaloids - chemistry Alkaloids - toxicity Animals Binding Sites Biological and medical sciences Brain - drug effects Brain - metabolism Carbon Radioisotopes Carrier Proteins - antagonists & inhibitors Carrier Proteins - metabolism Cell Line, Tumor Citalopram - analogs & derivatives Citalopram - chemical synthesis Citalopram - chemistry Citalopram - toxicity Contrast media. Radiopharmaceuticals Dopamine - pharmacology Female Macaca mulatta Male Medical sciences Membrane Glycoproteins - antagonists & inhibitors Membrane Glycoproteins - metabolism Membrane Transport Proteins Molecular Structure Nerve Tissue Proteins Norepinephrine - pharmacology Pharmacology. Drug treatments Radioligand Assay Rats Rats, Sprague-Dawley Serotonin - pharmacology Serotonin Plasma Membrane Transport Proteins Serotonin Uptake Inhibitors Tomography, Emission-Computed Intravenous administration Rat Ligand Central nervous system Monkey Carbon Isotopes Oxygen heterocycle Reuptake inhibitor Blood brain barrier Tissue Ex vivo Scintigraphic agent Primates Carbon 11 Bicyclic compound Aromatic compound Chemical synthesis Carrier protein Catalytic reaction Radiolabelling Serotonin Palladium Complexes Rodentia Aminoether Stille reaction In vitro Biological activity In vivo Vertebrata Biological fixation Mammalia Animal Distribution Tertiary amine Fluorine Organic compounds Iodomethane Pharmacokinetics Positron emission tomography Brain (vertebrata)
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Summary:	Three serotonin reuptake inhibitors where the 5-cyano group in citalopram [1-(3-dimethylamino-propyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile ( 1)] was replaced with a methyl, acetyl and piperidinyl carbonyl group, respectively, were synthesized. In a Stille reaction applying [ 11C]methyl iodide the labelled compound [5-methyl- 11C]{3-[1-(4-fluorophenyl)-5-methyl-1,3-dihydroisobenzofuran-1-yl]-propyl}-dimethylamine ( [ 11C]-2 ) was synthesized in 60–90% radiochemical yield. [5-carbonyl- 11C]{1-[1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]-1-piperidin-1-yl-methanone} ( [ 11C]-3 ) was synthesized in 62% radiochemical yield in a palladium mediated cross-coupling reaction utilizing [ 11C]carbon monoxide. The specific activity of [ 11C]-2 was highly dependent on whether the corresponding trimethyltin or tributyltin precursor was applied. In ex vivo rodent studies compound [ 11C]-2 exhibited a good blood–brain barrier (BBB) penetration whereas [ 11C]-3 did not. The brain distribution of [ 11C]-2 was investigated in a non-human primate using PET. There was a rapid uptake of radioactivity into the brain. Accumulation of the radiotracer was in agreement with the known distribution of serotonin transporters. The maximal thalamus to cerebellum ratio of 1.3 was reached after 85 min and the specific binding was partly blocked after pre-treatment with citalopram. Thus, [ 11C]-2 does not exhibit appropriate properties as radioligand for visualization of the serotonin transporter in vivo. Graphic
ISSN:	0968-0896 1464-3391
DOI:	10.1016/S0968-0896(03)00307-9