Novel CXCR4-Targeted Radioligands with Improved Tumor Uptake and Therapeutic Efficacy

Radioligands targeting the C-X-C Chemokine Receptor 4 (CXCR4) are promising for the diagnosis and therapy of multiple tumor types. The therapeutic efficacy of radiopharmaceutical therapy can be enhanced by albumin binders, which modulate the plasma half-life of radioligands and can increase tumor uptake. We report a novel class of CXCR4-targeting radioligands conjugated to non-covalent albumin binders with improved tumor uptake and prolonged tumor retention in a lymphoma model. Four 4-phenylbutyric acid (4-PBA) derivatives with p-MeO, p-Cl, p-Br, or p-I substituents were selected as albumin-binding motifs and coupled to a novel CXCR4-binding cyclic peptide. All non-radioactive standards were obtained with high purity (>95%) and showed high specific binding to CXCR4 as measured by the radioligand competition assay. Four peptides were labeled with [177Lu]LuCl3, with >94% radiochemical purity. Biodistribution and longitudinal SPECT imaging studies showed that variations in albumin binder substituents modulated the plasma half-life of CXCR4-targeting radioligands and improved tumor uptake. [177Lu]Lu-6, a peptide coupled to a 4-BrPBA albumin binder, showed high tumor uptake and tumor-to-organ ratios optimal for therapeutic studies. [177Lu]Lu-6 tumor uptake reached 23.6 ± 4.57% injected activity per gram (% IA/g) at 24 h post-injection, with persistent uptake (12.3 ± 2.04 % IA/g) after 120 h. Blood and kidney uptake were 0.28 ± 0.03 and 1.14 ± 0.08 % IA/g at 24 h, respectively. In a therapy study, [177Lu]Lu-6 (15, 30, and 60 MBq) resulted in potent tumor growth inhibition and increased overall survival in a Z138 xenograft model in comparison to the control and [177Lu]Lu-Pentixather groups (p < 0.05). Novel CXCR4 radioligands coupled to albumin binders demonstrated high and prolonged tumor uptake in a CXCR4-expressing tumor model. [177Lu]Lu-6 achieved an excellent balance between maximizing tumor uptake while keeping the blood residence time sufficiently short to avoid excessive exposure to normal organs.