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

Abstract

A [18F]AlF-labeled somatostatin receptor (SSTR) antagonist was developed for imaging of neuroendocrine neoplasms (NENs), evaluated and compared with [68Ga]Ga-DOTA-TATE. [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 50~60min post-injection (p.i.). Normal organ biodistribution and tumor detectability were evaluated. [18F]AlF-NOTA-JR11(24~36GBq/μmol) was prepared within 30min 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 30min, and the internalization at 37°C of [18F]AlF-NOTA-JR11 (5.47 ± 0.32% at 60min) was significantly lower than [68Ga]Ga-DOTA-TATE (66.89 ± 1.62% at 60min). The affinity of [18F]AlF-NOTA-JR11 (Kd = 11.59 ± 1.31nM) was slightly lower than [68Ga]Ga-DOTA-TATE (Kd = 7.36 ± 1.02nM); [18F]AlF-NOTA-JR11 showed high uptake in tumor (9.02 ± 0.92 %ID/g at 60min p.i.) which can be blocked by 50μg of NOTA-JR11 (3.40 ± 1.64 %ID/g at 60min 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. 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.