Synthesis and preclinical evaluation of [18F]AlF-NOTA-Asp2-PEG2-JR11 as a novel antagonist radioligand for PET imaging of somatostatin receptor

Purpose Somatostatin receptor (SSTR) antagonists have recently emerged as preferable radiotracers for SSTR-targeted imaging and therapy. This study aimed to design a novel SSTR antagonist, [F-18]AlF-NOTA-Asp(2)-PEG(2)-JR11, and compare its preclinical performance with the previously reported antagonist, [F-18]AlF-NOTA-JR11, and the agonist [Ga-68]Ga-DOTA-TATE. Methods [F-18]AlF-NOTA-Asp(2)-PEG(2)-JR11 was synthesized via a one-step radiolabeling process involving [F-18]AlF chelation. The binding affinity, internalization, and cellular uptake were evaluated using AR42J/SSTR + cells. Biodistribution and PET/CT imaging were conducted in mice bearing xenografted AR42J/SSTR + or HCT116/SSTR- tumor xenografts. Results [F-18]AlF-NOTA-Asp(2)-PEG(2)-JR11 was manually synthesized within 30 min with an uncorrected radiochemical yield of 39.56 +/- 3.25% (n > 5) and radiochemical purity (RCP) exceeding 99% (n > 5). [F-18]AlF-NOTA-Asp(2)-PEG(2)-JR11 demonstrated excellent in vivo stability over 2 h (RCP > 95%). Among AR42J cells, [F-18]AlF-NOTA-Asp(2)-PEG(2)-JR11 exhibited high affinity, specific uptake, and low internalization, similar to [F-18]AlF-NOTA-JR11. Biodistribution and micro-PET/CT imaging studies revealed comparable tumor uptake between [F-18]AlF-NOTA-Asp(2)-PEG(2)-JR11 and [F-18]AlF-NOTA-JR11 (9.26 +/- 0.49 vs. 10.18 +/- 0.82%ID/g, p = 0.147) at 60 min post-injection (p.i), both were significantly higher than [Ga-68]Ga-DOTA-TATE (6.79 +/- 0.29%ID/g, p = 0.001). Co-injecting the corresponding inhibitor significantly reduced the tumor uptake of all three tracers. Notably, [F-18]AlF-NOTA-Asp(2)-PEG(2)-JR11 reached peak tumor uptake at 30 min p.i. and exhibited the lowest uptake and fastest clearance in most normal organs, including the kidney, bone, liver, and muscle, resulting in the highest and increasing tumor-to-background ratios (TBR) over time among the three tracers. Conclusion The synthesis of [F-18]AlF-NOTA-Asp(2)-PEG(2)-JR11 is efficient, with high radiochemical yield and RCP. [F-18]AlF-NOTA-Asp(2)-PEG(2)-JR11 exhibits excellent in vivo stability, high tumor uptake, and superior TBR, making it a promising potential tracer for imaging SSTR-positive tumors.