Development of a Ga-68 labeled PET tracer with short linker for prostate-specific membrane antigen (PSMA) targeting.Glu-Urea-Lys (GUL) derivatives have been reported as prostate-specific membrane antigen (PSMA) agent.  We developed derivatives of GUL conjugated with NOTA or DOTA via a thiourea linker and tested their feasibility as PSMA imaging agents after labeling with 68Ga.  NOTA-GUL and DOTA-GUL were synthesized and labeled with 68Ga using generator-eluted 68GaCl3 in 0.1 M HCl in the presence of 1 M NaOAc at pH 5.5.  The stabilities of 68Ga-labeled compounds in human serum were tested at 37.5 °C.  A competitive binding assay was performed using the PSMA-positive prostate cancer cell line 22Rv1 and [125I]MIP-1072 (PSMA-specific binding agent) as a tracer.  Biodistribution and micro-PET studies were performed using 22Rv1-xenograft BALB/c nude mice.  The radiolabeling efficiency of NOTA-GUL (>99%) was higher than that of DOTA-GUL (92%).  The IC50 of Ga-NOTA-GUL was 18.3 nM.  Tumor/muscle and tumor/blood uptake ratios of 68Ga-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of 68Ga-DOTA-GUL (16.1 and 31.1, respectively).  68Ga-NOTA-GUL showed specific uptake to PSMA positive tumor xenograft and was blocked by co-injection of the cold ligand.  In conclusion, we successfully synthesized 68Ga-NOTA-GUL and 68Ga-DOTA-GUL for prostate cancer imaging.  68Ga-NOTA-GUL showed better radiochemical and biodistribution results.  68Ga-NOTA-GUL may be a promising PSMA targeting radiopharmaceutical.
C
In the biodistribution study, tumor uptake of 68Ga-NOTA-GUL (5.40% ID/g) was higher than that of 68Ga-DOTA-GUL (4.66% ID/g) at 1 h.  Tumor/muscle and tumor/blood uptake ratios of 68Ga-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of 68Ga-DOTA-GUL (16.1 and 31.1, respectively).  The tumor/kidney uptake ratio of 68Ga-NOTA-GUL was 3.4-fold higher than that of 68Ga-DOTA-GUL.  68Ga-NOTA-GUL showed specific uptake to PSMA positive tumor xenograft and was blocked by co-injection of the cold ligand.  In conclusion, we successfully synthesized 68Ga-NOTA-GUL and 68Ga-DOTA-GUL for prostate cancer imaging.  68Ga-NOTA-GUL showed better radiochemical and biodistribution results.  68Ga-NOTA-GUL may be a promising PSMA targeting radiopharmaceutical.
68Ga-NOTA-GUL
In the biodistribution study, tumor uptake of 68Ga-NOTA-GUL (5.40% ID/g) was higher than that of 68Ga-DOTA-GUL (4.66% ID/g) at 1 h.  Tumor/muscle and tumor/blood uptake ratios of 68Ga-NOTA-GUL (31.8 and 135, respectively) were significantly higher than those of 68Ga-DOTA-GUL (16.1 and 31.1, respectively).  The tumor/kidney uptake ratio of 68Ga-NOTA-GUL was 3.4-fold higher than that of 68Ga-DOTA-GUL.  In conclusion, we successfully synthesized 68Ga-NOTA-GUL and 68Ga-DOTA-GUL for prostate cancer imaging. 
68Ga-DOTA-GUL