title: Synthesis and biological evaluation of novel carbon-11-labelled analogues of citalopram as potential radioligands for the serotonin transporter.
abstract: 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)C]methyl iodide the labelled compound [5-methyl-(11)C][3-[1-(4-fluorophenyl)-5-methyl-1,3-dihydroisobenzofuran-1-yl]-propyl]-dimethylamine ([(11)C]-2) was synthesized in 60-90% radiochemical yield. [5-carbonyl-(11)C][1-[1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl]-1-piperidin-1-yl-methanone] ([(11)C]-3) was synthesized in 62% radiochemical yield in a palladium mediated cross-coupling reaction utilizing [(11)C]carbon monoxide. The specific activity of [(11)C]-2 was highly dependent on whether the corresponding trimethyltin or tributyltin precursor was applied. In ex vivo rodent studies compound [(11)C]-2 exhibited a good blood-brain barrier (BBB) penetration whereas [(11)C]-3 did not. The brain distribution of [(11)C]-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, [(11)C]-2 does not exhibit appropriate properties as radioligand for visualization of the serotonin transporter in vivo.
authors.affiliation: PET & Cyclotron Unit 3982, Copenhagen University Hospital, Blegdamsvej 9, 2100, Copenhagen, Denmark. j.madsen@rh.dk
authors.forename: Jacob
authors.initials: J
authors.lastname: Madsen
authors.forename: Pinelopi
authors.initials: P
authors.lastname: Merachtsaki
authors.forename: Padideh
authors.initials: P
authors.lastname: Davoodpour
authors.forename: Mats
authors.initials: M
authors.lastname: Bergström
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.forename: Kim
authors.initials: K
authors.lastname: Andersen
authors.forename: Christian
authors.initials: C
authors.lastname: Thomsen
authors.forename: Lars
authors.initials: L
authors.lastname: Martiny
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
mesh_terms: D000107:Acetylation; D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D015283:Citalopram / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity*; D004298:Dopamine / Q000494:pharmacology; D005260:Female; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D014055:Tomography, Emission-Computed
chemical_list: D000470:Alkaloids; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D015283:Citalopram; D004298:Dopamine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat