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 [F-18]AlF-labeled somatostatin receptor (SSTR) antagonist was developed for imaging of neuroendocrine neoplasms (NENs), evaluated and compared with [Ga-68]Ga-DOTA-TATE. Method [F-18]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-18]AlF-NOTA-JR11 PET/MR imaging and [Ga-68]Ga-DOTA-TATE PET/CT were performed with ten patients of NEN at 50 similar to 60 min post-injection (p.i.). Normal organ biodistribution and tumor detectability were evaluated. Result [F-18]AlF-NOTA-JR11(24 similar to 36 GBq/mu mol) 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-18]AlF-NOTA-JR11 and [Ga-68]Ga-DOTA-TATE were 4.50 +/- 0.31 and 4.50 +/- 0.13 %AD/10(5) cells at 30 min, and the internalization at 37 degrees C of [F-18]AlF-NOTA-JR11 (5.47 +/- 0.32% at 60 min) was significantly lower than [Ga-68]Ga-DOTA-TATE (66.89 +/- 1.62% at 60 min). The affinity of [F-18]AlF-NOTA-JR11 (K-d = 11.59 +/- 1.31 nM) was slightly lower than [Ga-68]Ga-DOTA-TATE (K-d = 7.36 +/- 1.02 nM); [F-18]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 mu g 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-18]AlF-NOTA-JR11 (n = 67 vs. 1 only by [Ga-68]Ga-DOTA-TATE), and the uptakes of [F-18]AlF-NOTA-JR11 in majority normal organs were significantly lower than [Ga-68]Ga-DOTA-TATE. The target to nontarget of maximum of standard uptake value (SUVmax) of [F-18]AlF-NOTA-JR11 in liver lesions were significantly higher than those of [Ga-68]Ga-DOTA-TATE. Conclusion Qualitied [F-18]AlF-NOTA-JR11 is prepared conveniently with reasonable yield, and it can bind SSTR2 specifically with high affinity. Excellent imaging capability of [F-18]AlF-NOTA-JR11 for NENs is superior to [Ga-68]Ga-DOTA-TATE, especially in digestive system. It has a great potential for imaging of NENs.

Automated summary

[F-18]AlF-NOTA-JR11 was developed for imaging of NENs and compared with [Ga-68]Ga-DOTA-TATE. The study showed that [F-18]AlF-NOTA-JR11 had superior imaging capability for NENs compared to [Ga-68]Ga-DOTA-TATE, especially in the digestive system.