Synthesis and in vivo evaluation of gallium-68-labeled glycine and hippurate conjugates for positron emission tomography renography

The objective of this study was to evaluate four new 68Ga-labeled 1,4,7,10-cyclododeca-1,4,7,10-tetraacetic acid (DOTA)/1,4,7-triazacyclononane-1,4,7-triacetic acid derived (NODAGA)-glycine/hippurate conjugates and select a lead candidate for potential application in positron emission tomography (PET) renography. The non-metallated conjugates were synthesized by a solid phase peptide synthesis method. The 68Ga labeling was achieved by reacting an excess of the non-metallated conjugate with 68GaCl4− at pH −4.5 and 10-min incubation either at room temperature for NODAGA or 90 °C for DOTA. Radiochemical purity of all 68Ga conjugates was found to be >98%. 68Ga-NODAGA-glycine displayed the lowest serum protein binding (0.4%) in vitro among the four 68Ga conjugates. Biodistribution of 68Ga conjugates in healthy Sprague Dawley rats at 1-h post-injection revealed an efficient clearance from circulation primarily through the renal–urinary pathway with <0.2% of injected dose per gram remaining in the blood. The kidney/blood and kidney/muscle ratios of 68Ga-NODAGA-glycine were significantly higher than other 68Ga conjugates. On the basis of these results, 68Ga-NODAGA-glycine was selected as the lead candidate. 68Ga-NODAGA-glycine PET renograms obtained in healthy rats suggest 68Ga-NODAGA-glycine as a PET alternate of 99mTc-Diethylenetriaminepentaacetic acid (DTPA).