Bio-Evaluation of 99mTc-Labeled Homodimeric Chalcone Derivative as Amyloid-ß-Targeting Probe
Por:
Mann, Garima, Chauhan, Kanchan, Kumar, Vikas, Daksh, Shivani, Kumar, Nikhil, Thirumal, M., Datta, Anupama
Publicada:
1 ene 2022
Categoría:
Medicine (miscellaneous)
Resumen:
Chalcone derivatives have been successfully utilized for a range of biological applications and can cross the blood–brain barrier easily. ß-amyloid-specific bis-chalcone derivative, 6,9-bis(carboxymethyl)-14-(4-[(E)-3-(4-(dimethylamino)phenyl)acryloyl]phenoxy)-3-(2-[(2-(4-[(E)-3-(4-(dimethylamino)phenyl)acryloyl]phenoxy)ethyl)amino]-2-oxoethyl)-11-oxo-3,6,9,12-tetraazatetradecanoic acid, DT(Ch)2, was analyzed using molecular modeling to explain the binding modes of the ligand with amyloid fibril and monomer followed by 99mTc-complexation in 95% yield and 98.7% efficiency. High-binding specificity of the radiocomplex was established following in vitro evaluation against 100-fold excess of DT(Ch)2. 99mTc–DT(Ch)2 exhibited <3% trans-complexation in human serum after 24 h, indicating high stability. A fast clearance rate in pharmacokinetics studies displayed a biphasic pattern with t1/2(F) = 30 min ± 0.09 and t1/2(S) = 4 h 20 min ± 0.06. In vivo single-photon emission computed tomography (SPECT) imaging in rabbits reiterated the pharmacokinetics data with initially high brain uptake followed by rapid washout. Biodistribution studies confirmed the initial brain uptake as 1.16 ± 0.02% ID/g after 2 min and the brain2min/brain30min ratio was 3.74. Radioactivity distribution in the brain was >40% in the cingulate cortex followed by >25% in the hippocampus, a distribution pattern aligned to Alzheimer’s affected brain regions. Radiocomplex also displayed rapid plasma clearance followed by hepatobolic and renal modes of excretion. Copyright © 2022 Mann, Chauhan, Kumar, Daksh, Kumar, Thirumal and Datta.
Filiaciones:
Mann, Garima:
Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, New Delhi, India
Department of Chemistry, University of Delhi, New Delhi, India
Def Res & Dev Org, Inst Nucl Med & Allied Sci, New Delhi, India
Univ Delhi, Dept Chem, New Delhi, India
Chauhan, Kanchan:
Centro de Nanociencias y Nanotecnología, Universidad Nacional Autónoma de México, Ensenada, Mexico
Univ Nacl Autonoma Mexico, Ctr Nanociencias & Nanotecnol, Ensenada, Baja California, Mexico
Kumar, Vikas:
Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, New Delhi, India
Def Res & Dev Org, Inst Nucl Med & Allied Sci, New Delhi, India
Daksh, Shivani:
Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, New Delhi, India
Def Res & Dev Org, Inst Nucl Med & Allied Sci, New Delhi, India
Kumar, Nikhil:
Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, New Delhi, India
Def Res & Dev Org, Inst Nucl Med & Allied Sci, New Delhi, India
Thirumal, M.:
Department of Chemistry, University of Delhi, New Delhi, India
Univ Delhi, Dept Chem, New Delhi, India
Datta, Anupama:
Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, New Delhi, India
Def Res & Dev Org, Inst Nucl Med & Allied Sci, New Delhi, India
gold, Green Published, Gold, Green
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