NURA Research Group, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium; Radiopharmaceutical Research, Department of Pharmacy and Pharmacology, University of Leuven, Leuven, Belgium.
Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
Nucl Med Biol. 2023 Mar-Apr;118-119:108338. doi: 10.1016/j.nucmedbio.2023.108338. Epub 2023 Mar 29.
[F]AlF-NOTA-octreotide is an F-labeled somatostatin analogue which is a good clinical alternative for Ga-labeled somatostatin analogues. However, radiolabeled somatostatin receptor (SSTR) antagonists might outperform agonists regarding imaging sensitivity of neuroendocrine tumors (NETs). No direct comparison between the antagonist [F]AlF-NOTA-JR11 and the agonist [F]AlF-NOTA-octreotide as SSTR PET probes is available. Herein, we present the radiosynthesis of [F]AlF-NOTA-JR11 and compare its NETs imaging properties directly with the established agonist radioligand [F]AlF-NOTA-octreotide preclinically.
[F]AlF-NOTA-JR11 was synthesized in an automated synthesis module. The in vitro binding characteristics (IC) of [F]AlF-NOTA-JR11 and [F]AlF-NOTA-octreotide were evaluated and the in vitro stability of [F]AlF-NOTA-JR11 was determined in human serum. In vitro cell binding and internalization was performed with [F]AlF-NOTA-JR11 and [F]AlF-NOTA-octreotide using SSTR2 expressing cells and the pharmacokinetics were evaluated using μPET/CT in mice bearing BON1.SSTR2 tumor xenografts.
Excellent binding affinity for SSTR2 was found for [F]AlF-NOTA-octreotide (IC of 25.7 ± 7.9 nM). However, the IC value for [F]AlF-NOTA-JR11 (290.6 ± 71 nM) was 11-fold higher compared to [F]AlF-NOTA-octreotide, indicating lower affinity for SSTR2. [F]AlF-NOTA-JR11 was obtained in a good RCY (50 ± 6 %) but with moderate RCP of 94 ± 1 %. [F]AlF-NOTA-JR11 demonstrated excellent stability in human serum (>95 % after 240 min). 2.7-fold higher cell binding was observed for [F]AlF-NOTA-JR11 as compared to [F]AlF-NOTA-octreotide after 60 min. μPET/CT images demonstrated comparable pharmacokinetics and tumor uptake between [F]AlF-NOTA-JR11 (SUV: 3.7 ± 0.8) and [F]AlF-NOTA-octreotide (SUV: 3.6 ± 0.4).
[F]AlF-NOTA-JR11 was obtained in good RCY, albeit with a moderate RCP. The cell binding study showed significant higher binding of [F]AlF-NOTA-JR11 compared to [F]AlF-NOTA-octreotide, despite the higher IC value of AlF-NOTA-JR11. However, pharmacokinetics and in vivo tumor uptake was comparable for both radiotracers. Novel AlF-labeled derivatives of JR11 with higher SSTR2 affinity should be developed for increased tumor uptake and NET imaging sensitivity.
[F]AlF-NOTA-奥曲肽是一种 F 标记的生长抑素类似物，是 Ga 标记的生长抑素类似物的良好临床替代品。然而，放射性标记的生长抑素受体（SSTR）拮抗剂在神经内分泌肿瘤（NETs）的成像灵敏度方面可能优于激动剂。目前还没有 [F]AlF-NOTA-JR11 拮抗剂和已建立的激动剂放射性配体 [F]AlF-NOTA-奥曲肽作为 SSTR PET 探针之间的直接比较。在此，我们介绍了 [F]AlF-NOTA-JR11 的放射合成，并在临床前直接比较了其 NETs 成像特性与已建立的激动剂放射性配体 [F]AlF-NOTA-奥曲肽。
[F]AlF-NOTA-JR11 是在自动化合成模块中合成的。评估了 [F]AlF-NOTA-JR11 和 [F]AlF-NOTA-奥曲肽的体外结合特性（IC），并在人血清中测定了 [F]AlF-NOTA-JR11 的体外稳定性。使用 SSTR2 表达细胞进行了 [F]AlF-NOTA-JR11 和 [F]AlF-NOTA-奥曲肽的体外细胞结合和内化实验，并使用 μPET/CT 在携带 BON1.SSTR2 肿瘤异种移植的小鼠中评估了它们的药代动力学。
发现 [F]AlF-NOTA-奥曲肽对 SSTR2 具有极好的结合亲和力（IC 为 25.7±7.9 nM）。然而，[F]AlF-NOTA-JR11 的 IC 值（290.6±71 nM）比 [F]AlF-NOTA-奥曲肽高 11 倍，表明对 SSTR2 的亲和力较低。[F]AlF-NOTA-JR11 的 RCY 良好（50±6%），但 RCP 中等（94±1%）。[F]AlF-NOTA-JR11 在人血清中表现出极好的稳定性（>240 min 后>95%）。与 [F]AlF-NOTA-奥曲肽相比，[F]AlF-NOTA-JR11 在 60 min 后观察到细胞结合增加了 2.7 倍。μPET/CT 图像表明 [F]AlF-NOTA-JR11（SUV：3.7±0.8）和 [F]AlF-NOTA-奥曲肽（SUV：3.6±0.4）之间具有可比的药代动力学和肿瘤摄取。
尽管 [F]AlF-NOTA-JR11 的 IC 值较高，但 [F]AlF-NOTA-JR11 的 RCY 良好，RCP 中等。细胞结合研究表明，与 [F]AlF-NOTA-奥曲肽相比，[F]AlF-NOTA-JR11 的结合显著增加，尽管 [F]AlF-NOTA-JR11 的 IC 值较高。然而，两种放射性示踪剂的药代动力学和体内肿瘤摄取相当。应开发具有更高 SSTR2 亲和力的新型 AlF 标记 JR11 衍生物，以提高肿瘤摄取和 NET 成像灵敏度。
