68Ga-labeled ODAP-Urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent

• DOI: 10.1007/s00259-021-05486-x
• Publication Date: 2021-08-28T03:27:55Z
• Authors: Xiaojiang Duan; Zhen Cao; Hua Zhu; Chen Liu; Xiaojun Zhang; Jinming Zhang; Ya’nan Ren; Futao Liu; Xuekang Cai; Xiaoyi Guo; Zhen Xi; Martin G. Pomper; Zhi Yang; Yan Fan; Xing Yang
• Keywords: Glutamate Carboxypeptidase II; Male; Radiology, Nuclear Medicine and Imaging; Biochemistry; Mice; Biodistribution; 0302 clinical medicine; Urea; Tissue Distribution; Internal medicine; Cancer; Prostate cancer; Radiochemistry; Prostate Cancer; Prostate; 3. Good health; Nuclear chemistry; Chemistry; Oncology; Antigens, Surface; Metallurgy; Medicine; Receptor; Biotechnology; Pulmonary and Respiratory Medicine; Ligand (biochemistry); Gallium Radioisotopes; Yield (engineering); Role of Fibroblast Activation in Cancer Progression; 03 medical and health sciences; Advancements in Prostate Cancer Research; In vitro; Glutamate carboxypeptidase II; Cell Line, Tumor; Health Sciences; In vivo; Animals; Humans; Pharmacokinetics; Biology; Pharmacology; Amino Acids, Diamino; Prostatic Neoplasms; Development and Applications of Radiopharmaceuticals; Materials science; Positron-Emission Tomography; Nuclear medicine; Imaging agent

Abstract Purpose: Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here we report the synthesis of an optimized 68 Ga-labeled ODAP-Urea-based ligand, [ 68 Ga]Ga-P 137 , and first-in-human results. Methods: Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68 Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice bearing 22Rv1 prostate tumors by microPET. Lead compound [ 68 Ga]Ga-P 137 was evaluated for stability, cell uptake and biodistribution. PET imaging of [ 68 Ga]Ga-P 137 was performed in three patients head-to-head compared to [ 68 Ga]Ga-PSMA-617. Results : Ligands were synthesized in 11.1%-44.4% yield and >95% purity. They have high affinity to PSMA( K i of 0.13 NM to 5.47 nM). [ 68 Ga]Ga-P 137 was stable and hydrophilic. [ 68 Ga]Ga-P 137 showed higher uptake than [ 68 Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98 %ID/g vs 3.41 ± 1.31 %ID/g at 60 min post-injection. In humans studies, the normal organ biodistribution of [ 68 Ga]Ga-P 137 was grossly equivalent to that of [ 68 Ga]Ga-PSMA-617 except for within the urinary tract, in which [ 68 Ga]Ga-P 137 demonstrated lower uptake. Conclusion: The optimized ODAP-Urea-based ligand [ 68 Ga]Ga-P 137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [ 68 Ga]Ga-PSMA-617, in a preliminary, first-in-human study.