Design, Preclinical Evaluation, and Clinical Translation of [68Ga]Ga/[177Lu]Lu-JH120061, a Novel Radiopharmaceutical Targeting CXCR4

PURPOSE: We designed and synthesized a novel compound targeting CXCR4, JH120061. Using clinically established Pentixafor and Pentixather as references, we evaluated the potential of [68Ga]Ga/[177Lu]Lu-JH120061 in a series of preclinical and clinical studies. PATIENTS AND METHODS: Preclinical studies of [68Ga]Ga/[177Lu]Lu-JH120061 were conducted on CXCR4-expressing cell lines (HT1080-hCXCR4) and HT1080-hCXCR4 tumor-bearing mice. A head-to-head comparison of [68Ga]Ga-JH120061 with [68Ga]Ga-Pentixafor for PET/CT was conducted in patients with multiple myeloma (n = 5) and renal masses (n = 5). An expanded cohort of 53 patients with renal masses underwent [68Ga]Ga-JH120061 PET/CT to assess its performance in identifying renal malignancy. RESULTS: Preclinical studies revealed that JH120061 demonstrated high binding affinity for CXCR4, promising cellular uptake and retention. In a clinical study, [68Ga]Ga-JH120061 PET/CT detected more malignant lesions than [68Ga]Ga-Pentixafor (94 vs 81, P = 0.031) and showed significantly higher tumor uptake (SUVₘₐₓ 22.3 ± 12.9 vs. 9.4 ± 6.5, P < 0.001, at 60 min). Furthermore, [68Ga]Ga-JH120061 PET/CT exhibited excellent detectability for clear cell renal cell carcinoma (ccRCC), its tumor uptake was significantly higher than that in non-ccRCC (SUVₘₐₓ 28.9 ± 11.7 vs. 7.3 ± 2.4, P < 0.001). CONCLUSION: This study demonstrated that JH120061 may have excellent affinity for CXCR4. Notably, [68Ga]Ga-JH120061 PET/CT demonstrated a remarkable capability for detecting ccRCC. Future studies should further explore the potential of [68Ga]Ga/[177Lu]Lu-JH120061 in precision theranostics of CXCR4-positive tumors.