title: Chemical design of a radiolabeled gelatinase inhibitor peptide for the imaging of gelatinase activity in tumors.
abstract: Since elevated levels of gelatinases [matrix metalloproteinase (MMP)-2 and MMP-9] are associated with a poor prognosis in cancer patients, these enzymes are potential targets for tumor imaging. In the present study, a cyclic decapeptide, cCTTHWGFTLC (CTT), was selected as a mother compound because of its selective inhibitory activity toward gelatinases. For imaging gelatinase activity in tumors, we designed a CTT-based radiopharmaceutical taking into consideration that (1) the HWGF motif of the peptide is important for the activity, (2) hydrophilic radiolabeled peptides show low-level accumulation in the liver and (3) an increase in the negative charge of radiolabeled peptides is effective in reducing renal accumulation. Thus, a highly hydrophilic and negatively charged radiolabel, indiun-111-diethylenetriaminepentaacetic acid ((111)In-DTPA), was attached to an N-terminal residue distant from the HWGF motif ((111)In-DTPA-CTT). In MMP-2 inhibition assays, In-DTPA-CTT significantly inhibited the proteolytic activity in a concentration-dependent fashion. When injected into normal mice, (111)In-DTPA-CTT showed low levels of radioactivity in the liver and kidney. A comparison of the pharmacokinetic characteristics of (111)In-DTPA-CTT with those of other CTT derivatives having different physicochemical properties revealed that the increase in hydrophilicity and negative charge caused by the conjugation of (111)In-DTPA reduced levels of radioactivity in the liver and kidney. In tumor-bearing mice, a significant correlation was observed between the accumulation in the tumor as well as tumor-to-blood ratio of (111)In-DTPA-CTT and gelatinase activity. These findings support the validity of the chemical design of (111)In-DTPA-CTT for reducing accumulation in nontarget tissues and maintaining the inhibitory activity of the mother compound. Furthermore, (111)In-DTPA-CTT derivatives would be potential radiopharmaceuticals for the imaging of gelatinase activity in metastatic tumors in vivo.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Kyoto 606-8501, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hanaoka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mukai
authors.forename: Sayo
authors.initials: S
authors.lastname: Habashita
authors.forename: Daigo
authors.initials: D
authors.lastname: Asano
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Akizawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Iida
authors.forename: Keigo
authors.initials: K
authors.lastname: Endo
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Saga
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000201:enzymology*; D045744:Cell Line, Tumor; D015195:Drug Design; D004789:Enzyme Activation; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008657:Metabolic Clearance Rate; D051379:Mice; D009928:Organ Specificity; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; C523669:indium-111-DTPA-CTT; D004369:Pentetic Acid; D020780:Matrix Metalloproteinase 9