Development of Novel Radiogallium-Labeled Bone Imaging Agents Using Oligo-Aspartic Acid Peptides as Carriers

⁶⁸Ga (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 ⁶⁸Ga-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 ⁶⁷Ga, with the previously described ⁶⁷Ga-DOTA complex conjugated bisphosphonate, ⁶⁷Ga-DOTA-Bn-SCN-HBP. After synthesizing DOTA-(Asp)_n by a Fmoc-based solid-phase method, complexes were formed with ⁶⁷Ga, resulting in ⁶⁷Ga-DOTA-(Asp)_n with a radiochemical purity of over 95% after HPLC purification. In hydroxyapatite binding assays, the binding rate of ⁶⁷Ga-DOTA-(Asp)_n increased with the increase in the length of the conjugated aspartate peptide. Moreover, in biodistribution experiments, ⁶⁷Ga-DOTA-(Asp)₈, ⁶⁷Ga-DOTA-(Asp)₁₁, and ⁶⁷Ga-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 ⁶⁷Ga-DOTA-(Asp)_n was lower than that of ⁶⁷Ga-DOTA-Bn-SCN-HBP, blood clearance of ⁶⁷Ga-DOTA-(Asp)_n was more rapid. Accordingly, the bone/blood ratios of ⁶⁷Ga-DOTA-(Asp)₁₁ and ⁶⁷Ga-DOTA-(Asp)₁₄ were comparable with those of ⁶⁷Ga-DOTA-Bn-SCN-HBP. In conclusion, these data provide useful insights into the drug design of ⁶⁸Ga-PET tracers for the diagnosis of bone disorders, such as bone metastases.