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Synthesis, preclinical evaluation, and a pilot clinical imaging study of [18F]AlF-NOTA-JR11 for neuroendocrine neoplasms compared with [68Ga]Ga-DOTA-TATE

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Abstract

Purpose

A [18F]AlF-labeled somatostatin receptor (SSTR) antagonist was developed for imaging of neuroendocrine neoplasms (NENs), evaluated and compared with [68Ga]Ga-DOTA-TATE.

Method

[18F]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. [18F]AlF-NOTA-JR11 PET/MR imaging and [68Ga]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.

Result

[18F]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 [18F]AlF-NOTA-JR11 and [68Ga]Ga-DOTA-TATE were 4.50 ± 0.31 and 4.50 ± 0.13 %AD/105 cells at 30 min, and the internalization at 37 °C of [18F]AlF-NOTA-JR11 (5.47 ± 0.32% at 60 min) was significantly lower than [68Ga]Ga-DOTA-TATE (66.89 ± 1.62% at 60 min). The affinity of [18F]AlF-NOTA-JR11 (Kd = 11.59 ± 1.31 nM) was slightly lower than [68Ga]Ga-DOTA-TATE (Kd = 7.36 ± 1.02 nM); [18F]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 [18F]AlF-NOTA-JR11 (n = 67 vs. 1 only by [68Ga]Ga-DOTA-TATE), and the uptakes of [18F]AlF-NOTA-JR11 in majority normal organs were significantly lower than [68Ga]Ga-DOTA-TATE. The target to nontarget of maximum of standard uptake value (SUVmax) of [18F]AlF-NOTA-JR11 in liver lesions were significantly higher than those of [68Ga]Ga-DOTA-TATE.

Conclusion

Qualitied [18F]AlF-NOTA-JR11 is prepared conveniently with reasonable yield, and it can bind SSTR2 specifically with high affinity. Excellent imaging capability of [18F]AlF-NOTA-JR11 for NENs is superior to [68Ga]Ga-DOTA-TATE, especially in digestive system. It has a great potential for imaging of NENs.

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Funding

This work was financially supported by National Natural Science Foundation of China projects (81871386, 81671733) and Natural Science Foundation of Beijing Municipality (7171002).

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Authors and Affiliations

  1. 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

    Qing Xie, Teli Liu, Jing Ding, Nina Zhou, Xiangxi Meng, Hua Zhu, Nan Li, Jiangyuan Yu & Zhi Yang

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  1. Qing Xie
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Correspondence to Jiangyuan Yu or Zhi Yang.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by Ethics Committee of Beijing Cancer Hospital and Institute (permit 2,014,011,313 and 2020KT15). Informed consent was obtained from all individual participants included in the study.

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Xie, Q., Liu, T., Ding, J. et al. Synthesis, preclinical evaluation, and a pilot clinical imaging study of [18F]AlF-NOTA-JR11 for neuroendocrine neoplasms compared with [68Ga]Ga-DOTA-TATE. Eur J Nucl Med Mol Imaging 48, 3129–3140 (2021). https://doi.org/10.1007/s00259-021-05249-8

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