Development of novel radiogallium-labeled bone imaging agents using oligo-aspartic acid peptides as carriers

• Published in: PloS one Vol. 8; no. 12; p. e84335
• Main Authors: Ogawa, Kazuma, Ishizaki, Atsushi, Takai, Kenichiro, Kitamura, Yoji, Kiwada, Tatsuto, Shiba, Kazuhiro, Odani, Akira
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 31.12.2013; Public Library of Science (PLoS)
• Subjects: Accumulation; Acids; Aspartate; Aspartic acid; Background radiation; Binding; Binding sites; Biology; Biomedical materials; Blood; Bone and Bones - anatomy & histology; Bone and Bones - metabolism; Bone and Bones - pathology; Bone diseases; Bone imaging; Cancer metastasis; Cancer therapies; Chelation; Chemistry; Chromatography, High Pressure Liquid; Drug delivery systems; Drug development; Durapatite - metabolism; Fluorides; Gallium Radioisotopes - chemistry; Gallium Radioisotopes - pharmacokinetics; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - metabolism; High-performance liquid chromatography; Humans; Hydroxyapatite; Hydroxyapatites; Liquid chromatography; Medical imaging; Medicine; Metastases; Metastasis; Molecular Structure; NMR; Nuclear magnetic resonance; Peptides; Peptides - metabolism; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Purification; Radiochemistry; Radioisotopes; Solid-Phase Synthesis Techniques; Surgical implants; Tissues; Tomography; Tracers; Tumors; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0084335

(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.