title: Synthesis and evaluation of technetium-99m-labeled bioreductive pharmacophores conjugated with amino acids and peptides for tumor imaging.
abstract: Development of molecular imaging agents to target tumor has become a major trend in nuclear medicine. With the aim to develop new potential 99mTc-radiopharmaceuticals for targeting tumor, we have synthesized 5-nitroimidazolyl amino acids and RGD-coupled 2-nitroimidazoles. Technetium-99m radiolabeling with high radiochemical purity (>90%) was achieved for all the compounds. The radiolabeled complexes exhibited substantial in vitro stability in saline, serum, and histidine solution (10(-2) m). Cell binding studies in EAC and B16F10 cell lines also revealed rapid and comparatively high cellular internalization. Among all the compounds studied, the binding of 99mTc(CO)3-5 to B16F10 cells was moderately inhibited by the competitive peptide c[RGDfV], suggesting specificity of the radioligand toward αvβ3 receptor. However, no significant displacement of bound radioligand was observed when the binding of the 99mTc-labeled complexes to above cells was challenged with excess competitive peptide. Fluorescent microscopy study provided direct evidence of intracellular localization of 5(6)-carboxyfluorescein-labeled 2-nitroimidazolyl-RGD-peptide in αvβ3-positive B16F10 mouse melanoma cell line. The ligands caused only 8-13% of hemolysis toward rat erythrocytes at concentrations as high as 100 μm. Imaging and biodistribution studies were performed in Swiss albino mice bearing induced tumor. 99mTc-1 and 99mTc(CO)3-5 demonstrated a very favorable in vivo profile. Selective uptake and retention in tumor with encouraging tumor/muscle and tumor/blood ratio and significant cellular uptake of fluorescence-labeled-2-nitroimidazolyl RGD indicate the great potentiality of the pharmacophore for further evaluation as potential molecular imaging agent in cancer diagnosis.
authors.affiliation: Infectious Diseases and Immunology Division, Nuclear Medicine Department, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata, 700 032, India.
authors.forename: Rinku
authors.initials: R
authors.lastname: Baishya
authors.forename: Dipak K
authors.initials: DK
authors.lastname: Nayak
authors.forename: Sanmoy
authors.initials: S
authors.lastname: Karmakar
authors.forename: Sankha
authors.initials: S
authors.lastname: Chattopadhyay
authors.forename: Satbir S
authors.initials: SS
authors.lastname: Sachdeva
authors.forename: Bharat R
authors.initials: BR
authors.lastname: Sarkar
authors.forename: Shantanu
authors.initials: S
authors.lastname: Ganguly
authors.forename: Mita C
authors.initials: MC
authors.lastname: Debnath
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D045744:Cell Line, Tumor; D051379:Mice; D057054:Molecular Imaging; D009369:Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging* / Q000378:metabolism; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D017207:Rats, Sprague-Dawley
chemical_list: D000596:Amino Acids; D009842:Oligopeptides; D015609:Organotechnetium Compounds; C047981:arginyl-glycyl-aspartic acid
keywords: amino acids and peptides; bioreductive pharmacophore; technetium-99m labeling; tumor imaging