Melanoma, a malignant tumor derived from epidermal melanocytes, is the most serious form of skin cancer with high mortality, aggressiveness, therapeutic resistance, and predisposition for late metastasis. Novel theranostic agents for imaging and treatment of melanoma that allow identifying melanoma patients with high-risk primary lesions would facilitate further surveillance and possible adjuvant therapy. Very late antigen-4 (VLA-4) is a transmembrane noncovalent heterodimer overexpressed in melanoma tumors that is associated with tumor growth, angiogenesis, and metastasis by promoting adhesion and migration of cancer cells. The current study describes a VLA-4 targeting molecule, LLP2A, conjugated to a versatile, new chelator (Lumi804) that readily complexes radiolanthanides for targeted radiopharmaceutical therapy, along with Zr-89 for PET imaging. Lumi804 is an octadentate, macrocyclic compound based on four 1-hydroxypyridin-2-one (1,2-HOPO) coordinating units. This was conjugated with the high-affinity VLA-4 peptidomimetic ligand, LLP2A, and labeled with the following radiometals: Zr-89, Lu-177, and Tb-161 at room temperature under 30 min. Binding affinity of 89Zr-, 177Lu-, 161Tb-Lumi804-LLP2A for VLA-4 will be determined and compared in VLA-4-positive B16F10 mouse melanoma cells. The biodistribution of the Zr-89 analogue was determined by PET/CT and dissection with gamma counting in B16F10 subcutaneous tumor-bearing mice. Data for Zr-89 show VLA-4 mediated uptake in the B16F10 tumor-bearing mice. Biodistributions of the 177Lu- and 161Tb-Lumi804-LLP2A analogues are planned.

Novel theranostic agents for PET imaging and treatment of metastatic melanoma targeting very late antigen 4 (VLA-4) using a versatile chelator for Lu(III), Tb(III), and Zr(IV)

ACS Spring 2022

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