Abstract
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.
Highlights
Bone contains abundant proliferation factors, and is a convenient environment for tumors to metastasize and grow
Significant advances in imaging technologies such as X-ray computed tomography (CT) and magnetic resonance imaging (MRI) have been made during the last a few decades; because of its high sensitivity, nuclear medicine bone scanning is the optimal test for detecting bone metastases
The crude products were purified by reversed-phase (RP)-HPLC performed with a Hydrosphere 5C18 column (106150 mm; YMC, Kyoto, Japan) at a flow rate of 4 mL/min with an isocratic mobile phase of water containing 0.1% trifluoroacetic acid (TFA) [in the case of DOTA-(Asp)2] or with a Cosmosil 5C18-AR 300 column (106150 mm; Nacalai Tesque, Kyoto, Japan) at a flow rate of 4 mL/min with a 0–20% methanol gradient mobile phase of 0.1% TFA in water over 20 minutes [in the case of DOTA-(Asp)n (n = 5, 8, 11, or 14)], respectively
Summary
Bone contains abundant proliferation factors, and is a convenient environment for tumors to metastasize and grow. The accumulation of 99mTc-bisphoshonate complexes in bone must be derived from the binding of phosphonate groups in bisphosphonate to calcium (Ca2+) in hydroxyapatite crystals in bone, but the mechanism of high uptake to lesion sites has not been completely elucidated. 99mTc-bisphoshonate complexes cannot be isolated as well-defined single chemical species, but as mixtures of short- and long-chain oligomers, may reduce the efficacy of radiopharmaceuticals. Biological behaviors of these tracers are affected by the degree of ionization and by variable oligomer constitutions of preparations [11]. This drug concept is applicable to both 99mTc-complex radiopharmaceuticals and other radiometals [16,17,18,19,20,21,22,23,24,25,26]
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