Development of a Ga-68 labeled PET tracer with short linker for prostate-specific membrane antigen (PSMA) targeting

  • Bioorg Med Chem. 2018 May 15;26(9):2501-2507. doi: 10.1016/j.bmc.2018.04.014.
Sung-Hyun Moon  1 ,  Mee Kyung Hong  2 ,  Young Ju Kim  3 ,  Yun-Sang Lee  2 ,  Dong Soo Lee  2 ,  June-Key Chung  3 ,  Jae Min Jeong  4
Affiliations
  • 1. Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Republic of Korea; Department of Radiology, Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 2. Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Republic of Korea; Department of Nuclear Medicine, Seoul National University Hospital, Republic of Korea.
  • 3. Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Republic of Korea; Department of Nuclear Medicine, Seoul National University Hospital, Republic of Korea.
  • 4. Department of Nuclear Medicine, Institute of Radiation Medicine, Seoul National University College of Medicine, Republic of Korea; Cancer Research Institute, Seoul National University College of Medicine, Republic of Korea; Department of Nuclear Medicine, Seoul National University Hospital, Republic of Korea. Electronic address: [email protected].
PMID: 29655611 DOI: 10.1016/j.bmc.2018.04.014
Abstract

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. 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.

Keywords
DOTA-GUL; Gallium; Imaging probe; NOTA-GUL; PET; PSMA.
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