title: In vivo evaluation of a radiogallium-labeled bifunctional radiopharmaceutical, Ga-DOTA-MN2, for hypoxic tumor imaging.
abstract: On the basis of the findings obtained by X-ray crystallography of Ga-DOTA chelates and the drug design concept of bifunctional radiopharmaceuticals, we previously designed and synthesized a radiogallium-labeled DOTA chelate containing two metronidazole moieties, (67)Ga-DOTA-MN2, for hypoxic tumor imaging. As expected, (67)Ga-DOTA-MN2 exhibited high in vivo stability, although two carboxyl groups in the DOTA skeleton were conjugated with metronidazole moieties. In this study, we evaluated (67/68)Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors. (67)Ga-labeling of DOTA-MN2 with (67)GaCl(3) was achieved with high radiochemical yield (>85%) by 1-min of microwave irradiation (50 W). The pharmacokinetics of (67)Ga-DOTA-MN2 were examined in FM3A tumor-bearing mice, and compared with those of (67)Ga-DOTA-MN1 containing one metronidazole unit and (67)Ga-DOTA. Upon administration, (67)Ga-DOTA-MN2 exhibited higher accumulation in the implanted tumors than (67)Ga-DOTA. Tumor-to-blood ratios of (67)Ga-DOTA-MN2 were about two-fold higher than those of (67)Ga-DOTA-MN1. Autoradiographic analysis showed the heterogeneous localization of (67)Ga-DOTA-MN2 in the tumors, which corresponds to hypoxic regions suggested by well-established hypoxia marker drug, pimonidazole. Furthermore, in positron emission tomography (PET) study, the tumors of mice administered (68)Ga-labeled DOTA-MN2 were clearly imaged by small-animal PET at 1 h after administration. This study demonstrates the potential usefulness of (67/68)Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors and suggests that two functional moieties, such as metronidazole, can be conjugated to radiogallium-DOTA chelate without reducing the complex stability. The present findings provide useful information about the chemical design of radiogallium-labeled radiopharmaceuticals for PET and single photon emission computed tomography (SPECT) studies.
authors.affiliation: Department of Biomolecular Recognition Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Sano
authors.forename: Mayumi
authors.initials: M
authors.lastname: Okada
authors.forename: Hayato
authors.initials: H
authors.lastname: Hisada
authors.forename: Kenta
authors.initials: K
authors.lastname: Shimokawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Saji
authors.forename: Minoru
authors.initials: M
authors.lastname: Maeda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Mukai
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D005710:Gallium Radioisotopes / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D006573:Heterocyclic Compounds, 1-Ring / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D000860:Hypoxia; D015674:Mammary Neoplasms, Animal / Q000000981:diagnostic imaging*; D008795:Metronidazole / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008809:Mice, Inbred C3H; D049268:Positron-Emission Tomography; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D008795:Metronidazole; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid