Very late antigen 4 (VLA-4) is a transmembrane non-covalent heterodimer, which is overexpressed in certain types of cancer cells and is associated with tumor growth and metastasis. Previous studies have shown that 177Lu-DOTA-PEG4-LLP2A provides marginal therapeutic efficacy in B16F10 melanoma tumor-bearing mice. Terbium-161 [6.89 d half-life, β−:100%, Eβmax = 594 keV, γ emissions: 48.9 keV (17.0%) and 74.6 keV (10.2%)] has physical and chemical properties that are comparable to the clinically established isotope Lu-177 [6.65 d half-life, β−:100%, Eβmax = 497 keV, γ emission: 208 keV (10.4%)]. In contrast with Lu-177 however, Tb-161 decays with co-emission of ~12 Auger and conversion electrons (≤50 keV, vs. ~1 keV for Lu-177), and along with its low energy β− particle, results in a higher total electron-to-photon ratio of Tb-161 (5.9) than Lu-177 (4.8). For internalizing radiopharmaceutical therapy agents, higher abundance of low-energy electrons may enhance the killing of tumor cells. Bifunctional derivatives of the macrocyclic chelator DOTA represent the current state-of-the-art for radiolanthanide-based agents. However, fully in-cage chelation of lanthanides by DOTA is slow and sensitive to the presence of transition metal impurities (e.g., Zn2+, Cu2+, Fe3+), which lowers the achievable effective molar activity of radiopharmaceutical therapeutic agents. In contrast, Lumi804 is a recently developed macrocyclic bifunctional chelator that more readily chelates metal ions that prefer 8-coordination, such as Zr4+ and Lu3+. A major advantage of Lumi804 over DOTA is its propensity for efficient radiolabeling at lower temperature (25 oC) and at lower pH (more favorable to aqueous metal ion stability) within 30 minutes. Herein we present our comparative study of molar activities achieved using MU Research Reactor produced Tb-161 (160Gd(n,g)161Gd - 161Tb) and Lu-177 (176Lu(n,g)177Lu) labeled DOTAGA-PEG4-LLP2A (where GA = glutaric acid; 1) vs. Lumi804-PEG4-LLP2A (2). Thus far, only small activity batches of Tb-161 have been produced (&lt; 1 GBq), meaning the effects of trace metal contaminants become more important. Our preliminary labeling results showed quantitative Tb-161 labeling of compound 2 in 5 minutes at room temperature (pH 4-5). In contrast, compound 1 required heating to 95 oC for 30 minutes (pH 4-5). The highest molar activity reached thus far for 1 and 2are 40 mCi/nmol and 200 mCi/nmol, respectively. Studies with Lu-177 labeling are ongoing.

Tb-161 and Lu-177 labeling chemistry of DOTAGA-PEG4-LLP2A and Lumi804-PEG4-LLP2A as VLA-4 targeted theranostics

ACS Spring 2022

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