Comparative Kidney Uptake of Nanobody-Based PET Tracers Labeled with Various Fluorine-18-Labeled Prosthetic Groups

作者：Colleen P. Olkowski, Falguni Basuli, Bruna Fernandes, Behnaz Ghaemi, Jianfeng Shi, Hongwei H. Zhang, Joshua Μ. Farber, Freddy E. Escorcia, Peter L. Choyke, Orit Jacobson · 发表于：Molecular Pharmaceutics · 年份：2024 · DOI：10.1021/acs.molpharmaceut.4c01101 · 被引用次数：13 · 研究领域：Monoclonal and Polyclonal Antibodies Research、Radiopharmaceutical Chemistry and Applications、CAR-T cell therapy research

Nanobodies, or single-domain antibody fragments, are promising candidates for molecular imaging due to their small size, rapid tissue penetration, and high target specificity. However, a significant challenge in their use is high renal uptake and retention, which can limit the therapeutic efficacy and complicate image interpretation. This study compares five different fluorine-18-labeled prosthetic groups for nanobodies, aiming to optimize pharmacokinetics and minimize kidney retention while maintaining tumor targeting. Using an epidermal growth factor receptor (EGFR) targeting nanobody as a model, two labeling approaches were evaluated; direct labeling of RESCA (with and without polyethylene glycol (PEG))-conjugated nanobody using Al[ 18 F]F and indirect labeling using ([ 18 F]F-fluoropyridine ([ 18 F]F-FPy)-based prosthetic groups (site-specific and nonsite-specific). Labeled nanobodies were characterized in vitro for binding affinity and cell uptake with in vivo behavior assessed in EGFR + A431 tumor-bearing mice using PET imaging and biodistribution studies. Labeling with Al[ 18 F]F showed high renal retention, which was partially mitigated by PEGylation. However, PEGylation also led to a decreased tumor uptake, particularly with longer PEG chains. Labeling using [ 18 F]F-FPy prosthetic groups exhibited the most favorable pharmacokinetics, with rapid renal clearance and minimal kidney retention while maintaining high tumor uptake. These constructs showed excellent tumor-t...