Al18FNOTA-GABA-KE108的制备及初步生物学评价

Preparation and Preliminary Biological Evaluation of Al18FNOTA-GABA-KE108

  • 摘要: 放射性核素标记的生长抑素类似物可与神经内分泌肿瘤(NETs)细胞表面的生长抑素受体(SSTR)特异性结合,因此可用作NETs显像或治疗的靶点。本研究通过双功能螯合剂1,4,7-三氮杂环壬烷-1,4,7-三乙酸(NOTA)螯合Al18F复合物设计合成了一种新型靶向SSTR的放射性探针Al18FNOTA-GABA-KE108。Al18FNOTA-GABA-KE108的合成时间为30 min左右,标记率为60%~80%(未校正),经Sep-pak C-18 light柱纯化后,放化纯度>95%。Al18FNOTA-GABA-KE108呈水溶性(lg P=-1.67±0.07),在生理盐水及小牛血清中孵育2 h后放化纯度>95%。在SSTR阳性AR42J和BON1肿瘤细胞中,Al18FNOTA-GABA-KE108探针与受体结合的亲和力(Kd)分别为(1.34±0.60)、(1.45±0.51) μmol/L,且能被特异性抑制,展现出较高的SSTR靶向能力。Al18FNOTA-GABA-KE108在正常KM小鼠肝脏和肾脏中具有高放射性聚集,说明探针主要通过肝肾代谢,在SSTR表达较高的肾上腺和胰腺中有较高的放射性浓集,在BON1荷瘤鼠体内也具有相同的代谢途径,且在血液和肌肉中的本底低,而在肿瘤部位有较高的放射性摄取,具有高的靶与非靶比。以上结果为进一步研究Al18F复合物标记的生长抑素类似物作为生长抑素受体阳性肿瘤显像剂提供了实验依据。

     

    Abstract: Radionuclide labeled somatostatin analogs can specifically bind to somatostatin receptors (SSTRs) on the cell surface of neuroendocrine tumors (NETs) cells, so they can be used as a target for imaging or therapy of nets. In this study, a novel 18F-radiolabeled targeting SSTRs probe Al18FNOTA-GABA-KE108 was designed and synthesized, which linked 18F nuclide coupling bifunctional chelator (NOTA). Al18FNOTA-GABA-KE108 was obtained with high radiolabeling rate (60%-80%) and the total synthesis time was 30 min. After purification, the radiochemical purity was more than 95%. And the stability in vitro is excellent. In the SSTR-positive AR42J and BON1 tumor cells, the binding affinity between Al18FNOTA-GABA-KE108 and receptor (Kd=(1.34±0.60) μmol/L and (1.45±0.51) μmol/L, respectively) could be specifically inhibited, demonstrating high SSTR targeting ability. In normal KM mice and AR42J tumor bearing mice, Al18FNOTA-GABA-KE108 has high radioactivity accumulation in liver and kidney, which both indicate the same metabolic pattern. And a high uptake of radioactivity in adrenal gland and a high ratio of tumor to muscle uptake, similarly, demonstrate that Al18FNOTA-GABA-KE108 has excellent performance. These preliminary results provide some experimental basis for further study of Al18F labeled somatostatin analogues (KE108 complex) as tumor probes in the diagnosis of SSTR-positive tumors.

     

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