GDMPA Key Laboratory for Quality Control and Evaluation of Radiopharmaceuticals, PET Center and Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Department of Nuclear Medicine, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
Bioconjug Chem. 2023 Nov 15;34(11):2133-2143. doi: 10.1021/acs.bioconjchem.3c00442. Epub 2023 Oct 24.
Molecular imaging and targeted radiotherapy with radiolabeled fibroblast activation protein inhibitor (FAPI) targeting peptide probes hold great potential for enhancing the clinical management of patients with FAP-expressing cancers. However, the high cost of PET probes has prompted us to search for new FAP-targeting single-photon imaging agents. In this study, HYNIC-Glc-FAPT is synthesized and radiolabeled with technetium-99m using tricine/EDDA or dimer tricine as coligands to produce [Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT and [Tc]Tc-tricine-HYNIC-Glc-FAPT. Both [Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT and [Tc]Tc-tricine-HYNIC-Glc-FAPT were effectively synthesized with an excellent radiochemistry yield (both >97%, = 6) in a single-step technique, and their stability in PBS and human serum was satisfactory. Compared to [Tc]Tc-tricine-HYNIC-Glc-FAPT, [Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT exhibited a more hydrophilic nature with a log of -3.53 ± 0.12. In vitro cellular uptake and blocking assays, internalization, efflux experiments, and affinity experiments all suggested a mechanism with high FAP-specificity and affinity. SPECT imaging and biodistribution of [Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT demonstrated sustained high tumor uptake in BALB/c nude mice bearing U87MG tumors for 6 h. It demonstrated a long-range retention characteristic and more rapid clearance ability from nontarget organs. Collectively, we successfully synthesized [Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT and [Tc]Tc-tricine-HYNIC-Glc-FAPT, and the excellent targeting properties of [Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT suggest a potential diagnostic value in future clinical studies for advanced-stage FAP-expressing malignancies, especially in prognostic evaluation of tumors for it low price and convenient source.
用放射性标记的成纤维细胞激活蛋白抑制剂（FAPI）靶向肽探针进行分子成像和靶向放射治疗，为表达 FAP 的癌症患者的临床管理提供了巨大的潜力。然而，正电子发射断层扫描（PET）探针的高成本促使我们寻找新的 FAPI 靶向单光子成像剂。在这项研究中，合成了 HYNIC-Glc-FAPT，并使用 tricine/EDDA 或二聚体 tricine 作为共配体，用锝-99m 放射性标记，生成 [Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT 和 [Tc]Tc-tricine-HYNIC-Glc-FAPT。两种 [Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT 和 [Tc]Tc-tricine-HYNIC-Glc-FAPT 均通过一步法有效合成，放射化学收率均大于 97%（均为 6），在 PBS 和人血清中的稳定性均令人满意。与 [Tc]Tc-tricine-HYNIC-Glc-FAPT 相比，[Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT 具有更亲水的性质，其 logP 值为-3.53±0.12。细胞摄取和阻断实验、内化实验、外排实验和亲和实验均表明，其具有高特异性和高亲和力的 FAP 机制。[Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT 的 SPECT 成像和生物分布研究表明，在荷 U87MG 肿瘤的 BALB/c 裸鼠中，其在 6 小时内持续具有高肿瘤摄取。它表现出长程保留特征和更快的从非靶器官清除能力。综上所述，我们成功合成了 [Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT 和 [Tc]Tc-tricine-HYNIC-Glc-FAPT，[Tc]Tc-tricine/EDDA-HYNIC-Glc-FAPT 的优异靶向特性表明其在未来 FAP 表达恶性肿瘤的临床研究中具有潜在的诊断价值，特别是在肿瘤预后评估方面，因为其价格低廉，来源方便。
