Synthesis, preclinical evaluation, and the first-in-human study of [18F]AlF-NOTA-FZSR for neuroendocrine neoplasms compared with [68Ga]Ga-DOTA-NOC and [68Ga]Ga-DOTA-TATE

To improve the detection of neuroendocrine neoplasms (NENs), we developed a series of octreotide-based somatostatin receptor (SSTR)-targeted probes and sought to identify an optimal candidate through preclinical and clinical head-to-head evaluation versus [ 68 Ga]Ga-DOTA-TATE and [ 68 Ga]Ga-DOTA-NOC. Eight original probes were synthesised and radiolabelled with 68 Ga or 18 F. The in vitro stability of the probes in saline and human serum, as well as their in vivo stability through urine sampling, was determined by radio-high-performance liquid chromatography (radio-HPLC). Micro-PET/CT imaging was performed in AR42J xenograft-bearing mice 60 min after injection of the radiotracers via the tail vein. On the basis of preclinical screening, [ 18 F]AlF-NOTA-FZSR was selected for clinical PET/CT and directly compared with [ 68 Ga]Ga-DOTA-TATE and [ 68 Ga]Ga-DOTA-NOC in patients with NENs. All probes were successfully synthesised and radiolabelled with high radiochemical purity (> 98%) and showed good in vitro and in vivo stability (> 95% for 2 h). Among them, [ 18 F]AlF-NOTA-FZSR demonstrated the highest tumour uptake on micro-PET/CT in the AR42J model (41.17 ± 2.50%ID/g at 60 min), exceeding that of [ 68 Ga]Ga-DOTA-NOC (29.67 ± 1.53%ID/g) and [ 68 Ga]Ga-DOTA-TATE (11.2 ± 1.13%ID/g). In clinical PET/CT studies, [ 18 F]AlF-NOTA-FZSR detected lesions not identified by either [ 68 Ga]Ga-DOTA-NOC or [ 68 Ga]Ga-DOTA-TATE. In a patient with liver metastases, [ 18 F]AlF-NOTA-FZSR showed higher lesion uptake than [ 68 Ga]Ga-DOTA-TATE at both early and delayed imaging. At the early imaging time point (45–60 min post-injection), the SUVmax values of [ 68 Ga]Ga-DOTA-TATE and [ 18 F]AlF-NOTA-FZSR were 8.3 and 8.9, respectively. A delayed scan was performed approximately 30 min after the initial imaging session, the corresponding SUVmax values were 10.6 and 8.8, respectively, with a liver background SUVmax of 6.9. In a patient with metastatic pulmonary neuroendocrine carcinoma, [ 18 F]AlF-NOTA-FZSR (SUVmax = 13.6 for rib, SUVmax = 9.1 for thoracic vertebrae) also demonstrated markedly greater sensitivity than [ 68 Ga]Ga-DOTA-NOC (SUVmax = 1.4 for rib, SUVmax = 1.8 for thoracic vertebrae) for detecting bone metastases. We developed several novel SSTR-targeted probes with favourable physicochemical properties and identified [ 18 F]AlF-NOTA-FZSR as the most promising candidate. Compared with [ 68 Ga]Ga-DOTA-TATE and [ 68 Ga]Ga-DOTA-NOC, [ 18 F]AlF-NOTA-FZSR showed superior lesion detection in patients with NENs, supporting its potential for clinical translation.