Zhang Xuran, Lee Kyo Chul, Choi Joon Young, Lee Kyung-Han, Choe Yearn Seong
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
Division of Applied RI, Korea Institute of Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
Mol Pharm. 2025 Feb 3;22(2):906-917. doi: 10.1021/acs.molpharmaceut.4c01080. Epub 2024 Dec 30.
Fibroblast activation protein inhibitors (FAPIs) labeled with gallium-68 and lutetium-177 show potential for use in the diagnosis and treatment of various cancers expressing FAP. However, Lu-labeled FAPIs often exhibit short tumor retention time, limiting their therapeutic applications. To improve tumor retention, we synthesized three radiolabeled dimeric FAPIs, [F], [Cu], and [Ga]. These were prepared by chelating Al[F]F to 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)-l-glutamic acid (E)-(FAPI) and copper-64 or gallium-68 to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-E-(FAPI). NOTA-E-(FAPI) and DOTA-E-(FAPI) showed higher binding affinities for FAP compared with that of FAPI-04 (IC = 0.47 and 0.16 nM vs 0.89 nM, respectively). All radioligands were synthesized in high decay-corrected radiochemical yields (59-96%) and were stable in fetal bovine serum and phosphate-buffered saline. The more hydrophilic radioligand, [Ga], was selected for cellular uptake studies, which confirmed FAP-specific uptake. Positron emission tomography imaging and ex vivo biodistribution studies in U87MG tumor-bearing mice revealed high tumor uptake of all three radioligands, with significant blocking observed after preinjection of FAPI-04. [Cu] and [Ga] exhibited favorable in vivo pharmacokinetics compared to those of [F]. Notably, [Ga] showed lower normal organ uptake than did the other two radioligands, and moreover, it exhibited higher, more prolonged tumor uptake than its monomeric counterpart [Ga]Ga-FAPI-04 over a 3 h period, suggesting its potential as a promising FAP-specific theranostic radioligand.
用镓 - 68和镥 - 177标记的成纤维细胞活化蛋白抑制剂（FAPIs）在表达FAP的各种癌症的诊断和治疗中显示出应用潜力。然而，镥标记的FAPIs通常表现出较短的肿瘤滞留时间，限制了它们的治疗应用。为了提高肿瘤滞留率，我们合成了三种放射性标记的二聚体FAPIs，即[F]、[Cu]和[Ga]。它们是通过将Al[F]F螯合到1,4,7 - 三氮杂环壬烷 - 1,4,7 - 三乙酸（NOTA）-L - 谷氨酸（E）-（FAPI）上，以及将铜 - 64或镓 - 68螯合到1,4,7,10 - 四氮杂环十二烷 - 1,4,7,10 - 四乙酸（DOTA）-E - （FAPI）上制备的。与FAPI - 04相比，NOTA - E - （FAPI）和DOTA - E - （FAPI）对FAP表现出更高的结合亲和力（IC分别为0.47和0.16 nM，而FAPI - 04为0.89 nM）。所有放射性配体均以高衰变校正放射化学产率（59 - 96%）合成，并且在胎牛血清和磷酸盐缓冲盐水中稳定。选择亲水性更强的放射性配体[Ga]进行细胞摄取研究，该研究证实了FAP特异性摄取。在荷U87MG肿瘤小鼠中的正电子发射断层扫描成像和离体生物分布研究显示，所有三种放射性配体在肿瘤中的摄取量都很高，在预先注射FAPI - 04后观察到明显的阻断作用。与[F]相比，[Cu]和[Ga]表现出良好的体内药代动力学。值得注意的是，[Ga]在正常器官中的摄取低于其他两种放射性配体，此外，在3小时内，它在肿瘤中的摄取高于其单体对应物[Ga]Ga - FAPI - 04，并且持续时间更长，这表明它作为一种有前景的FAP特异性诊疗放射性配体具有潜力。
