Department of Nuclear Medicine, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital & Institute, No. 52 Fu-Cheng Rd., Beijing, 100142, China.
Eur J Nucl Med Mol Imaging. 2021 Sep;48(10):3129-3140. doi: 10.1007/s00259-021-05249-8. Epub 2021 Feb 25.
A [F]AlF-labeled somatostatin receptor (SSTR) antagonist was developed for imaging of neuroendocrine neoplasms (NENs), evaluated and compared with [Ga]Ga-DOTA-TATE.
[F]AlF-NOTA-JR11 was synthesized manually and qualified with high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS). The cellular uptake, internalization, and saturation binding were performed with HEK293-SSTR2 cells. Biodistribution and micro-PET imaging were carried out with HEK293-SSTR2 tumor-bearing mice. [F]AlF-NOTA-JR11 PET/MR imaging and [Ga]Ga-DOTA-TATE PET/CT were performed with ten patients of NEN at 50~60 min post-injection (p.i.). Normal organ biodistribution and tumor detectability were evaluated.
[F]AlF-NOTA-JR11(24~36 GBq/μmol) was prepared within 30 min and 51.35 ± 3.30% (n > 10)of radiochemical yield. The radiochemical purity was 98.74 ± 1.24% (n > 10). Two stereoisomers were found and confirmed by LC-MS. The cellular uptake of [F]AlF-NOTA-JR11 and [Ga]Ga-DOTA-TATE were 4.50 ± 0.31 and 4.50 ± 0.13 %AD/10 cells at 30 min, and the internalization at 37 °C of [F]AlF-NOTA-JR11 (5.47 ± 0.32% at 60 min) was significantly lower than [Ga]Ga-DOTA-TATE (66.89 ± 1.62% at 60 min). The affinity of [F]AlF-NOTA-JR11 (K = 11.59 ± 1.31 nM) was slightly lower than [Ga]Ga-DOTA-TATE (K = 7.36 ± 1.02 nM); [F]AlF-NOTA-JR11 showed high uptake in tumor (9.02 ± 0.92 %ID/g at 60 min p.i.) which can be blocked by 50 μg of NOTA-JR11 (3.40 ± 1.64 %ID/g at 60 min p.i.); the result was coincident with micro-PET imaging. Imaging study of NEN patients showed that more lesions were found only by [F]AlF-NOTA-JR11 (n = 67 vs. 1 only by [Ga]Ga-DOTA-TATE), and the uptakes of [F]AlF-NOTA-JR11 in majority normal organs were significantly lower than [Ga]Ga-DOTA-TATE. The target to nontarget of maximum of standard uptake value (SUVmax) of [F]AlF-NOTA-JR11 in liver lesions were significantly higher than those of [Ga]Ga-DOTA-TATE.
Qualitied [F]AlF-NOTA-JR11 is prepared conveniently with reasonable yield, and it can bind SSTR2 specifically with high affinity. Excellent imaging capability of [F]AlF-NOTA-JR11 for NENs is superior to [Ga]Ga-DOTA-TATE, especially in digestive system. It has a great potential for imaging of NENs.
研发一种 [F]AlF 标记的生长抑素受体（SSTR）拮抗剂，用于神经内分泌肿瘤（NEN）的成像，并与 [Ga]Ga-DOTA-TATE 进行评估和比较。
手动合成 [F]AlF-NOTA-JR11，并通过高效液相色谱（HPLC）和液质联用（LC-MS）进行质量合格检测。使用 HEK293-SSTR2 细胞进行细胞摄取、内化和饱和结合实验。使用荷 HEK293-SSTR2 肿瘤的小鼠进行生物分布和 micro-PET 成像实验。在注射后 50~60 分钟（p.i.），对 10 例 NEN 患者进行 [F]AlF-NOTA-JR11 PET/MR 成像和 [Ga]Ga-DOTA-TATE PET/CT 检查。评估正常器官的生物分布和肿瘤的可探测性。
[F]AlF-NOTA-JR11（24~36GBq/μmol）可在 30 分钟内制备完成，放射化学产率大于 51.35 ± 3.30%（n > 10）。放射化学纯度大于 98.74 ± 1.24%（n > 10）。通过 LC-MS 发现并确证了两种立体异构体。[F]AlF-NOTA-JR11 和 [Ga]Ga-DOTA-TATE 的细胞摄取率在 30 分钟时分别为 4.50 ± 0.31 和 4.50 ± 0.13 %AD/10 细胞，[F]AlF-NOTA-JR11 的内化率（60 分钟时为 5.47 ± 0.32%）明显低于 [Ga]Ga-DOTA-TATE（60 分钟时为 66.89 ± 1.62%）。[F]AlF-NOTA-JR11 的亲和力（K = 11.59 ± 1.31nM）略低于 [Ga]Ga-DOTA-TATE（K = 7.36 ± 1.02nM）；[F]AlF-NOTA-JR11 在肿瘤中表现出高摄取（60 分钟 p.i.时为 9.02 ± 0.92%ID/g），可被 50μg NOTA-JR11 阻断（60 分钟 p.i.时为 3.40 ± 1.64%ID/g）；这与 micro-PET 成像结果一致。NEN 患者的成像研究表明，[F]AlF-NOTA-JR11 仅发现 67 个病灶（而 [Ga]Ga-DOTA-TATE 仅发现 1 个病灶），且 [F]AlF-NOTA-JR11 在大多数正常器官中的摄取明显低于 [Ga]Ga-DOTA-TATE。[F]AlF-NOTA-JR11 在肝脏病变中的最大标准摄取值（SUVmax）的靶/非靶比值明显高于 [Ga]Ga-DOTA-TATE。
[F]AlF-NOTA-JR11 可方便地进行质量合格检测，以合理的产率制备，可特异性结合 SSTR2 并具有高亲和力。[F]AlF-NOTA-JR11 对 NENs 的出色成像能力优于 [Ga]Ga-DOTA-TATE，特别是在消化系统中。其在 NENs 成像方面具有很大的潜力。
