title: Synthesis, physicochemical and biological studies of technetium-99m labeled tacrine derivative as a diagnostic tool for evaluation of cholinesterase level.
abstract: In the present work the synthesis and physicochemical investigations of new tacrine analogues labeled with technetium-99m are reported. All obtained novel radioconjugates showed high stability in the presence of an excess of standard amino acids cysteine or histidine, as well as in human serum. Lipophilicity (LogD values) of these compounds is within the range from 0.92 to 1.56. For the selected radioconjugate99mTc(NS3)(CN-NH(CH2)7Tac) (LogD=1.56) the biological activity studies in the course of inhibition of acetylcholinesterase action have been performed (IC50=45.0nM, estimated by means of Ellman's method). Biodistribution studies of this compound showed its uptake in brain on the level of 0.07%ID/g and its clearance through the hepatic and renal route in comparable degree. The ascertained presence of the radioconjugate in brain indicates its possibility to cross the blood-brain barrier. Molecular modeling of99mTc(NS3)(CN-NH(CH2)7Tac) radioconjugate showed that the main structural fragment is tacrine moiety which is responsible for most interactions within catalytic and peripheral active sites and provides the anti-acetylcholinesterase activity. The99mTc(NS3)(CN-NH(CH2)7Tac) radioconjugate may be considered to be a diagnostic tool for patients suffering from Alzheimer's disease as well as a marker to determine the physiological condition of liver and intestines.
authors.affiliation: Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Gniazdowska
authors.affiliation: Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland. Electronic address: p.kozminski@ichtj.waw.pl.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Koźmiński
authors.affiliation: Department of Bioanalysis and Drug Analysis, Medicinal University of Warsaw, Warsaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Wasek
authors.affiliation: Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Bajda
authors.affiliation: Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, Lodz, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Sikora
authors.affiliation: Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, Lodz, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Mikiciuk-Olasik
authors.affiliation: Laboratory of Radiopharmacy, Department of Pharmaceutical Chemistry, Drug Analyses and Radiopharmacy, Medical University, Lodz, Poland. Electronic address: pawel.szymanski@umed.lodz.pl.
authors.forename: Paweł
authors.initials: P
authors.lastname: Szymański
mesh_terms: D000818:Animals; D002802:Cholinesterases / Q000032:analysis* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013619:Tacrine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D013619:Tacrine; D013667:Technetium; D002802:Cholinesterases
keywords: Biodistribution; Cholinesterase inhibitor; Molecular modeling studies; Radiopharmaceuticals technetium-99m; Tacrine