title: Development of novel radiogallium-labeled bone imaging agents using oligo-aspartic acid peptides as carriers.
abstract: (68)Ga (T 1/2 = 68 min, a generator-produced nuclide) has great potential as a radionuclide for clinical positron emission tomography (PET). Because poly-glutamic and poly-aspartic acids have high affinity for hydroxyapatite, to develop new bone targeting (68)Ga-labeled bone imaging agents for PET, we used 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a chelating site and conjugated aspartic acid peptides of varying lengths. Subsequently, we compared Ga complexes, Ga-DOTA-(Asp)n (n = 2, 5, 8, 11, or 14) with easy-to-handle (67)Ga, with the previously described (67)Ga-DOTA complex conjugated bisphosphonate, (67)Ga-DOTA-Bn-SCN-HBP. After synthesizing DOTA-(Asp)n by a Fmoc-based solid-phase method, complexes were formed with (67)Ga, resulting in (67)Ga-DOTA-(Asp)n with a radiochemical purity of over 95% after HPLC purification. In hydroxyapatite binding assays, the binding rate of (67)Ga-DOTA-(Asp)n increased with the increase in the length of the conjugated aspartate peptide. Moreover, in biodistribution experiments, (67)Ga-DOTA-(Asp)8, (67)Ga-DOTA-(Asp)11, and (67)Ga-DOTA-(Asp)14 showed high accumulation in bone (10.5 ± 1.5, 15.1 ± 2.6, and 12.8 ± 1.7% ID/g, respectively) but were barely observed in other tissues at 60 min after injection. Although bone accumulation of (67)Ga-DOTA-(Asp)n was lower than that of (67)Ga-DOTA-Bn-SCN-HBP, blood clearance of (67)Ga-DOTA-(Asp)n was more rapid. Accordingly, the bone/blood ratios of (67)Ga-DOTA-(Asp)11 and (67)Ga-DOTA-(Asp)14 were comparable with those of (67)Ga-DOTA-Bn-SCN-HBP. In conclusion, these data provide useful insights into the drug design of (68)Ga-PET tracers for the diagnosis of bone disorders, such as bone metastases.
authors.affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ishizaki
authors.affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Takai
authors.affiliation: Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Tatsuto
authors.initials: T
authors.lastname: Kiwada
authors.affiliation: Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiba
authors.affiliation: Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Odani
mesh_terms: D001842:Bone and Bones / Q000033:anatomy & histology* / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D017886:Durapatite / Q000378:metabolism*; D005710:Gallium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D060327:Solid-Phase Synthesis Techniques
chemical_list: D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D010455:Peptides; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C017645:polyaspartate; D017886:Durapatite