title: Design of Ga-DOTA-based bifunctional radiopharmaceuticals: two functional moieties can be conjugated to radiogallium-DOTA without reducing the complex stability.
abstract: From the X-ray crystal structures of Ga-DOTA chelates, we were able to deduce that two free carboxylate groups of the radiogallium-DOTA complex may be utilized for coupling to functional moieties that recognize molecular targets for in vivo imaging without reducing the radiogallium-complex stability. Thus, we designed 2,2'-[4,10-bis(2-{[2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl]amino}-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl]diacetic acid (DOTA-MN2) (7), employing a metronidazole moiety as the recognition site of hypoxic lesions, based on the drug design concept of bifunctional radiopharmaceuticals. Coupling of DOTA-bis(tert-butyl)ester 5 with 1-(2-aminoethyl)-2-methyl-5-nitroimidazole dihydrochloride, followed by deprotection, afforded the required 7 (DOTA-MN2). (67)Ga-labeling was carried out by reaction of DOTA-MN2 with (67)Ga-citrate. When (67)Ga-DOTA-MN2 was incubated in phosphate-buffered saline or mouse plasma, no measurable decomposition occurred over a 24-h period. In biodistribution experiments in NFSa tumor-bearing mice, (67)Ga-DOTA-MN2 displayed not only a significant tumor uptake, but also rapid blood clearance and low accumulations in nontarget tissues, resulting in high target-to-nontarget ratios of radioactivity. These results indicate the potential benefits of the drug design of (67)Ga-DOTA-MN2. The present findings provide helpful information for the development of radiogallium-labeled radiopharmaceuticals for SPECT and PET studies.
authors.affiliation: Department of Biomolecular Recognition Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. mukai@phar.kyushu-u.ac.jp
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mukai
authors.forename: Jun
authors.initials: J
authors.lastname: Suwada
authors.forename: Kohei
authors.initials: K
authors.lastname: Sano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Okada
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yamamoto
authors.forename: Minoru
authors.initials: M
authors.lastname: Maeda
mesh_terms: D000818:Animals; D015195:Drug Design; D004355:Drug Stability; D005260:Female; D005354:Fibrosarcoma / Q000000981:diagnostic imaging*; D005710:Gallium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D008795:Metronidazole / Q000737:chemistry / Q000493:pharmacokinetics; D051379:Mice; D008809:Mice, Inbred C3H; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*
chemical_list: D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D007093:Imidazoles; D019275:Radiopharmaceuticals; C543313:gallium(67)-2,2'-(4,10-bis(2-((2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid; D008795:Metronidazole