Department of Chemistry and Institute for Drug Discovery, Purdue University, West Lafayette, Indiana 47907, United States.
MorphImmune, Inc., 1281 Win Hentschel Blvd, West Lafayette, Indiana 47906, United States.
J Med Chem. 2024 Jul 25;67(14):11827-11840. doi: 10.1021/acs.jmedchem.4c00448. Epub 2024 Jul 16.
Fibroblast activation protein (FAP) has attracted considerable attention as a possible target for the radiotherapy of solid tumors. Unfortunately, initial efforts to treat solid tumors with FAP-targeted radionuclides have yielded only modest clinical responses, suggesting that further improvements in the molecular design of FAP-targeted radiopharmaceutical therapies (RPT) are warranted. In this study, we report several advances on the previously described FAP6 radioligand that increase tumor retention and accelerate healthy tissue clearance. Seven FAP6 derivatives with different linkers or albumin binders were synthesized, radiolabeled, and investigated for their effects on binding and cellular uptake. The radioligands were then characterized in 4T1 tumor-bearing Balb/c mice using both single-photon emission computed tomography (SPECT) and biodistribution analyses to identify the conjugate with the best tumor retention and tumor-to-healthy organ ratios. The results reveal an optimized FAP6 radioligand that exhibits efficacy and safety properties that potentially justify its translation into the clinic.
成纤维细胞激活蛋白（FAP）作为实体瘤放射治疗的潜在靶点引起了广泛关注。不幸的是，最初用 FAP 靶向放射性核素治疗实体瘤的尝试仅产生了适度的临床反应，这表明有必要进一步改进 FAP 靶向放射性药物治疗（RPT）的分子设计。在这项研究中，我们报告了先前描述的 FAP6 放射性配体的几项进展，这些进展增加了肿瘤的保留和加速了健康组织的清除。合成了七种具有不同连接子或白蛋白结合物的 FAP6 衍生物，对其结合和细胞摄取的影响进行了放射性标记和研究。然后，使用单光子发射计算机断层扫描（SPECT）和生物分布分析在 4T1 荷瘤 Balb/c 小鼠中对放射性配体进行了表征，以确定具有最佳肿瘤保留和肿瘤与健康器官比值的缀合物。结果揭示了一种经过优化的 FAP6 放射性配体，其具有的疗效和安全性特征可能使其具有转化为临床应用的潜力。
