Development and first-in-human study of PSMA-targeted PET tracers with improved pharmacokinetic properties

• Published in: European journal of nuclear medicine and molecular imaging 2024-07, Vol.51 (9), p.2819-2832
• Main Authors: Hou, Haodong, Pan, Yuan, Wang, Yanzhi, Ma, Yuze, Niu, Xiaobing, Sun, Suan, Hou, Guihua, Tao, Weijing, Gao, Feng
• Format: Article
• Language: English
• Subjects: Accumulation; Affinity; Animals; Antigens, Surface - metabolism; Binding; Biocompatibility; Biodistribution; Bladder; Cardiology; Cell Line, Tumor; Computed tomography; Dipeptides - chemistry; Dipeptides - pharmacokinetics; Gallium Radioisotopes - pharmacokinetics; Glutamate Carboxypeptidase II - metabolism; Heterocyclic Compounds, 1-Ring - chemistry; Heterocyclic Compounds, 1-Ring - pharmacokinetics; Humans; Imaging; In vivo methods and tests; Kidneys; Lesions; Male; Medical imaging; Medicine; Medicine & Public Health; Metabolic pathways; Metabolism; Metastases; Mice; Nuclear Medicine; Oncology; Original Article; Orthopedics; Pharmacokinetics; Phenylalanine; Positron emission; Positron Emission Tomography Computed Tomography - methods; Positron-Emission Tomography - methods; Prostatic Neoplasms - diagnostic imaging; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - radiotherapy; Quinoline; Radiation; Radioactive Tracers; Radiochemical analysis; Radiochemistry; Radiology; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Side effects; Tissue Distribution; Toxicity; Tumors
• ISSN: 1619-7070; 1619-7089; 1619-7089
• DOI: 10.1007/s00259-024-06726-6

Purpose A series of new 68 Ga-labeled tracers based on [ 68 Ga]Ga-PSMA-617 were developed to augment the tumor-to-kidney ratio and reduce the activity accumulation in bladder, ultimately minimize radiation toxicity to the urinary system. Methods We introduced quinoline group, phenylalanine and decanoic acid into different tracers to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Their binding affinity onto LNCaP cells was determined through in vitro saturation assays and competition binding assays. In vivo metabolic study, PET imaging and biodistribution experiment were performed in LNCaP tumor-bearing B-NSG male mice. The most promising tracer was selected for first-in-human study. Results Four radiotracers were synthesized with radiochemical purity (RCP) > 95% and molar activity in a range of 20.0-25.5 GBq/μmol. The binding affinities ( K i ) of TWS01, TWS02 to PSMA were in the low nanomolar range ( 20 nM (59.42 nM for TWS03 and 37.14 nM for TWS04). All radiotracers exhibited high stability in vivo except [ 68 Ga]Ga-TWS03. Micro PET/CT imaging and biodistribution analysis revealed that [ 68 Ga]Ga-TWS02 enabled clear tumor visualization in PET images at 1.5 h post-injection, with higher tumor-to-kidney ratio (T/K, 0.93) and tumor-to-muscle ratio (T/M, 107.62) compared with [ 68 Ga]Ga-PSMA-617 (T/K: 0.39, T/M: 15.01) and [ 68 Ga]Ga-PSMA-11 (T/K: 0.15, T/M: 24.00). In first-in-human study, [ 68 Ga]Ga-TWS02 effectively detected PCa-associated lesions including primary and metastatic lesions, with lower accumulation in urinary system, suggesting that [ 68 Ga]Ga-TWS02 might be applied in the detection of bladder invasion, with minimized radiation toxicity to the urinary system. Conclusion Introduction of quinoline group, phenylalanine and decanoic acid into different tracers can modulate the binding affinity and pharmacokinetics of PSMA in vivo. [ 68 Ga]Ga-TWS02 showed high binding affinity to PSMA, excellent pharmacokinetic properties and clear imaging of PCa-associated lesions, making it a promising radiotracer for the clinical diagnosis of PCa. Moreover, TWS02 with a chelator DOTA could also label 177 Lu and 225 Ac, which could be used for PCa treatment without significant side effects. Trial registration The clinical evaluation of this study was registered On October 30, 2021 at https://www.chictr.org.cn/ (No: ChiCTR2100052545).