title: Chemical design of (99m)Tc-labeled probes for targeting osteogenic bone region.
abstract: Radionuclide bone imaging using polynuclear (99m)Tc complexes of bisphosphonates is the most common clinical practice in nuclear medicine. However, the improvement in the contrast between normal and osteogenic bone regions has been required. Herein we reported a new (99m)Tc-labeled compound considering the increased vascular permeability of osteogenic region. We selected penta-d-Asp as both a targeting motif to hydroxyapatite (HA) and a molecular size modifier, and two penta-d-Asp molecules were conjugated with the two carboxylate residues of ethylene dicysteine (EC) selected as the (99m)Tc chelating moiety to prepare EC-[(d-Asp)5]2. The molecular size, HA binding, and pharmacokinetics of (99m)Tc-EC-[(d-Asp)5]2 in normal mice and model rats bearing osteogenic tumor were compared to those of (99m)Tc-MDP and (99m)Tc-EC with one (d-Asp)5 motif, (99m)Tc-EC-(d-Asp)5. The molecular size of (99m)Tc-EC-[(d-Asp)5]2 was higher than that of (99m)Tc-MDP and (99m)Tc-EC-(d-Asp)5 when determined by permeability of the (99m)Tc-compounds through a membrane filter (10 kDa). The HA binding of (99m)Tc-EC-[(d-Asp)5]2 was higher than and similar to that of (99m)Tc-EC-(d-Asp)5 and (99m)Tc-MDP. (99m)Tc-EC-[(d-Asp)5]2 exhibited significantly lower accumulation in normal bone of mice than did (99m)Tc-MDP. In osteogenic tumor bearing model rats, (99m)Tc-EC-[(d-Asp)5]2 accumulated in the osteogenic and normal bone region similar to and lower than (99m)Tc-MDP, respectively. Although further studies including the chain length of d-Asp are required, these findings indicated that the present chemical design of (99m)Tc-labeled probe would be applicable to develop (99m)Tc-labeled probes for selective imaging of osteogenic bone region as well as develop therapeutic agents using therapeutic radionuclides such as (90)Y, (177)Lu, (186)Re, or (188)Re and cytotoxic agents to osteogenic bone tumor region.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 263-8675, Japan.
authors.forename: Mashiho
authors.initials: M
authors.lastname: Yanagi
authors.forename: Tomoya
authors.initials: T
authors.lastname: Uehara
authors.forename: Yukie
authors.initials: Y
authors.lastname: Uchida
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kiyota
authors.forename: Mai
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higaki
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Akizawa
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Hanaoka
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Arano
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000737:chemistry*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D015335:Molecular Probes / Q000737:chemistry*; D015609:Organotechnetium Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D014018:Tissue Distribution
chemical_list: D015335:Molecular Probes; D015609:Organotechnetium Compounds