Abstract Prostate-specific membrane antigen (PSMA) PET imaging is widely used for diagnosing and staging prostate cancer, yet the currently approved 68Ga- and 18F-labeled tracers are limited by short half-lives and high urinary excretion, which can obscure small pelvic lesions. To overcome these challenges, 64Cu-RAX301 was developed as a high-affinity PSMA PET tracer designed for improved biochemical stability and extended imaging flexibility. The RAX301 precursor and its natCu-RAX301 analog were synthesized with high purity, and radiolabeling with 64Cu was optimized to achieve high molar activity (≥2000 mCi/μmol) and radiochemical purity (95%), and remaining stable for over 48 hours post-formulation. Surface plasmon resonance revealed sub-picomolar binding affinity (Kd 1 pM) for both the precursor and natCu-RAX301, markedly stronger than PSMA-617 (22 pM). Consistent with this, cell-based assays showed two-fold higher affinity, 1.5-fold greater uptake, and four-fold higher internalization compared with 64Cu-PSMA-617 (≈80% vs. ≈20%). In LNCaP xenograft mice, 64Cu-RAX301 demonstrated intense and persistent tumor uptake, with tumor-to-muscle ratios exceeding one hundred at 4 hours post-injection. PET imaging in Macaca fascicularis revealed primarily renal clearance with minimal uptake in other organs. In a first-in-human study of ten patients with metastatic castration-resistant prostate cancer (mCRPC), sequential PET/CT scans were performed first with 68Ga-PSMA-11 (5 mCi; imaging at 1 hour post-injection) and then with 64Cu-RAX301 (5 mCi; imaging at 4 and 24 hours post-injection), separated by 1-7 days. 64Cu-RAX301 detected all lesions identified by 68Ga-PSMA-11 while providing higher lesion uptake and superior tumor-to-background contrast. Notably, 64Cu-RAX301 revealed numerous additional small lesions at various sites, including pelvic lymph node metastases that were frequently missed by 68Ga-PSMA-11 due to early bladder activity. The tracer exhibited an excellent safety profile with no significant adverse events. Collectively, these preclinical and early clinical findings demonstrate that 64Cu-RAX301 possesses ultra-high PSMA affinity, favorable pharmacokinetics, and enhanced lesion visualization compared with 68Ga-PSMA-11, supporting its potential as a next-generation PSMA PET imaging agent with improved sensitivity and diagnostic performance in metastatic prostate cancer. Ongoing clinical studies aim to further define its diagnostic impact and broader clinical utility. Citation Format: Fei Chen, Min Hong, Xupeng Hu, Yang Cao, Jie Li, Zhao Li, Shuanglong Liu, Guangzhou Han, Suping Li, Gang Chen. Development and clinical evaluation of 64Cu-RAX301: A next-generation PSMA PET tracer for enhanced detection of metastatic prostate cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2610.
Chen et al. (Fri,) studied this question.