¹⁸F-labeled somatostatin analogs for somatostatin receptors (SSTRs) targeted PET imaging of neuroendocrine tumors (NETs)

Purpose: A novel F-18-radiolabeled somatostatin analogue, [(AlF)-F-18]NODA-MPAA-HTA, was synthesized and evaluated for positron emission tomography (PET) imaging of Neuroendocrine tumors (NETs). [(AlF)-F-18]NODA-MPAA-HTA was designed and synthesized by conjugating F-18 nuclide with a modified KE108 peptide, a somatostatin analog with high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), through coupling a bifunctional chelator (NODA) to target somatostatin receptor (SSTR) positive tumors.Methods: The amino group of KE108 peptide, a SSTRs-targeting pharmacophore, was conjugated with the carboxyl group of NODA by a condensation reaction to obtain the labeling precursor of [(AlF)-F-18]NODA-MPAA-HTA, in which its precursor was obtained through Fmoc solid-phase methods. A novel methodology for (AlF)-F-18 labeling of chelating agent-biomolecule conjugates was used to synthesize [(AlF)-F-18]NODA-MPAA-HTA. In vitro stabilities of [(AlF)-F-18]NODA-MPAA-HTA were evaluated by incubating it in saline or bovine serum for 2 h. Ex vivo biodistribution and in vivo imaging of [(AlF)-F-18]NODA-MPAA-HTA were further investigated to evaluate its SSTRs targeting ability and feasibility for the diagnosis of NETs using PET imaging.Results: [(AlF)-F-18]NODA-MPAA-HTA was synthesized using a one-step F-18-AlF labeling procedure resulting in moderate radiochemical yield (60-80 %, non-decay corrected) and high radiochemical purity (>95 %). It exhibited good hydrophilicity and excellent stability in vitro, with a molar activity of 122 GBq/mu mol. At 30 min and 60 min, the uptake of [(AlF)-F-18] NODA-MPAA-HTA by HEK293-SSTR2 cells was 5.47 +/- 0.97 %/105 cells and 12.11 +/- 0.32 %/105 cells, respectively. The affinity of [(AlF)-F-18]NODA-MPAA-HTA for SSTR2 was determined to be 8.77 +/- 1.14 nM. In micro-PET imaging of HEK293-SSTR2 tumor-bearing mice, [(AlF)-F-18]NODA-MPAA-HTA showed high tumor uptake of radioactivity and a high tumor-to-muscle ratio. Biodistribution results confirmed that radioactivity uptake in the tumor was significantly higher than that in the muscle by more than five-fold (P<0.001). Furthermore, the relatively low bone uptake of [(AlF)-F-18]NODA-MPAA-HTA suggested that defluorination did not occur in vivo. These preliminary results provide experimental evidence for further study of (AlF)-F-18-labeled somatostatin analogues as tumor probes for PET imaging of NETs.Conclusion: Fluorine-18 is widely used as a radionuclide for the production of radiopharmaceuticals for positron emission tomography (PET). Due to its short half-life (T1/2,109.8 min), its ease of production will facilitate the widespread dissemination of this radiopharmaceutical. A high-quality [(AlF)-F-18]NODA-MPAA-HTA was synthesized with satisfactory yield. This radiopharmaceutical demonstrated higher tumor uptake and better tumor-to-muscle contrast, resulting to excellent image quality. These findings suggest that the novel F-18-labeled somatostatin analogue, [(AlF)-F-18]NODA-MPAA-HTA, is a promising tool for PET imaging of NETs.