Synthesis, physicochemical and biological evaluation of tacrine derivative labeled with technetium-99m and gallium-68 as a prospective diagnostic tool for early diagnosis of Alzheimer’s disease

• Published in: Bioorganic chemistry 2019-10, Vol.91, p.103136-103136, Article 103136
• Main Authors: Gniazdowska, Ewa, Koźmiński, Przemysław, Halik, Paweł, Bajda, Marek, Czarnecka, Kamila, Mikiciuk-Olasik, Elżbieta, Masłowska, Katarzyna, Rogulski, Zbigniew, Cheda, Łukasz, Kilian, Krzysztof, Szymański, Paweł
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Gallium-68; PET/CT; Radiopharmaceuticals; SPECT/CT; Tacrine; Technetium-99m
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103136

[Display omitted] •New tacrine analogues were labeled with technetium-99m and gallium-68.•Novel radioconjugates showed high stability in biological solutions.•Molecular docking and biodistribution profile of radioconjugates.•New potential radiotracers for early diagnosis of Alzheimer’s disease. Design, physicochemical and biological studies of novel radioconjugates for the early diagnosis of Alzheimer's disease, based on the newly synthesized tacrine derivatives were performed. Novel tacrine analogues were labeled with technetium-99m and gallium-68. For all obtained radioconjugates ([99mTc]Tc-Hynic-(tricine)2NH(CH2)ntacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine, where n = 2–9 denotes the number of methylene groups CH2) the studies of physicochemical properties (lipophilicity, stability in the presence of an excess of standard amino acids cysteine or histidine, human serum and in cerebrospinal fluid) were performed. For two selected radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9Tac and [68Ga]Ga-DOTA-NH(CH2)9tacrine (characterized with the highest lipophilicity values) the biological tests (inhibition of cholinesterases action, molecular docking and biodistribution studies) have been performed. All novel radioconjugates showed high stability in biological solutions used. Both selected radioconjugates proved to be good inhibitors of cholinesterases and be able to cross the blood-brain barrier. Radioconjugates [99mTc]Tc-Hynic-(tricine)2NH(CH2)9tacrine and [68Ga]Ga-DOTA-NH(CH2)9tacrine fulfil the conditions for application in nuclear medicine. Radiopharmaceutical [68Ga]Ga-DOTA-NH(CH2)9tacrine, due to increased accuracy and improved sensitivity in PET imaging, may be better potential diagnostic tool for early diagnosis of Alzheimer’s disease.