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

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 (K_d = 11.59 ± 1.31 nM) was slightly lower than [⁶⁸Ga]Ga-DOTA-TATE (K_d = 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.