Abstract
Background: Somatostatin-based radiopharmaceuticals (e.g. [68Ga]Ga-DOTATATE and [177Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour patients with great success. Al18F-NOTA-octreotide, a promising 18F-labeled somatostatin analogue and potential alternative for 68Ga-DOTA-peptides, is under clinical evaluation [1]. Ideally, the same precursor (combination of chelator-linker-vector) can be used for production of both diagnostic and therapeutic radioprobes with very similar (e.g. Al18F/213Bi/177Lu) or identical (e.g. complementary Tb-radionuclides) pharmacokinetic properties, allowing accurate, personalised dosimetry estimation and radionuclide therapy of NET patients [2]. In this study we evaluate the versatile and highly effective chelator 3p-C-NETA [3] and present first results of radiosynthesis and stability of [18F]AlF-3p-C-NETA-TATE.
Methods: 3p-C-NETA was radiolabelled with diagnostic (68Ga, Al18F) or therapeutic (177Lu, 161Tb,213Bi) radionuclides at different temperatures. The in vitro stability of the corresponding radiocomplexes was determined in PBS and human serum at 37 °C. 3p-C-NETA-TATE was synthesised using standard solid-phase peptide synthesis and purified using HPLC. Al[18F]F-3p-C-NETA-TATE was synthesised in an automated AllInOne® synthesis module (Trasis, Belgium) and analysed using radio-HPLC. Finally, the in vitro stability of Al[18F]F-3p-C-NETA-TATE was evaluated in formulation buffer, PBS and human serum at 37 °C.
Results: 3p-C-NETA was efficiently labeled with 177Lu and 213Bi (RCY>95%) at room temperature and with 161Tb (>95%) and 68Ga (>90%) at 55 °C. Al18F-labeling required a higher temperature of 95 °C to achieve good yields (>85%). The 177Lu- and 161Tb-3p-C-NETA-complex showed excellent in vitro stability in both PBS and human serum over a period of eight days (97% intact). We also observed high in vitro stability up to 2 h for Al18F-3p-C-NETA (>93% intact in PBS and human serum). In contrast, 68Ga-3p-C-NETA was stable in PBS (>90% intact), but not in human serum (only 60% intact after 2h). Al18F-3p-C-NETA-TATE was obtained in good RCY (56%) and radiochemical purity (98%). Al18F-3p-C-NETA-TATE displayed excellent in vitro stability with >95% intact tracer after 4 hours in all tested conditions.
Conclusions: 3p-C-NETA is an excellent chelator that can be used for both targeted radionuclide therapy (177Lu, 213Bi and 161Tb) and diagnostic applications (Al18F) and has the potential to replace DOTA analogues in current clinical use. Al[18F]F-3p-C-NETA-TATE will be further evaluated using µPET/MRI imaging in healthy rats and SSTR2 positive tumour mice, in a head-to-head comparison with Al18F-NOTA-octreotide.
Reference
1. Pauwels E, et al. Eur J Nucl Med Mol Imaging 2020, 47, 3033–46.
2. Ahenkorah S, et al. Pharmaceutics 2021, 13, 599.
3. Chong HS, et al. Bioorg Med Chem Lett. 2008, 18, 3436–9.
Methods: 3p-C-NETA was radiolabelled with diagnostic (68Ga, Al18F) or therapeutic (177Lu, 161Tb,213Bi) radionuclides at different temperatures. The in vitro stability of the corresponding radiocomplexes was determined in PBS and human serum at 37 °C. 3p-C-NETA-TATE was synthesised using standard solid-phase peptide synthesis and purified using HPLC. Al[18F]F-3p-C-NETA-TATE was synthesised in an automated AllInOne® synthesis module (Trasis, Belgium) and analysed using radio-HPLC. Finally, the in vitro stability of Al[18F]F-3p-C-NETA-TATE was evaluated in formulation buffer, PBS and human serum at 37 °C.
Results: 3p-C-NETA was efficiently labeled with 177Lu and 213Bi (RCY>95%) at room temperature and with 161Tb (>95%) and 68Ga (>90%) at 55 °C. Al18F-labeling required a higher temperature of 95 °C to achieve good yields (>85%). The 177Lu- and 161Tb-3p-C-NETA-complex showed excellent in vitro stability in both PBS and human serum over a period of eight days (97% intact). We also observed high in vitro stability up to 2 h for Al18F-3p-C-NETA (>93% intact in PBS and human serum). In contrast, 68Ga-3p-C-NETA was stable in PBS (>90% intact), but not in human serum (only 60% intact after 2h). Al18F-3p-C-NETA-TATE was obtained in good RCY (56%) and radiochemical purity (98%). Al18F-3p-C-NETA-TATE displayed excellent in vitro stability with >95% intact tracer after 4 hours in all tested conditions.
Conclusions: 3p-C-NETA is an excellent chelator that can be used for both targeted radionuclide therapy (177Lu, 213Bi and 161Tb) and diagnostic applications (Al18F) and has the potential to replace DOTA analogues in current clinical use. Al[18F]F-3p-C-NETA-TATE will be further evaluated using µPET/MRI imaging in healthy rats and SSTR2 positive tumour mice, in a head-to-head comparison with Al18F-NOTA-octreotide.
Reference
1. Pauwels E, et al. Eur J Nucl Med Mol Imaging 2020, 47, 3033–46.
2. Ahenkorah S, et al. Pharmaceutics 2021, 13, 599.
3. Chong HS, et al. Bioorg Med Chem Lett. 2008, 18, 3436–9.
| Original language | English |
|---|---|
| Title of host publication | European Journal of Nuclear Medicine and Molecular Imaging |
| Subtitle of host publication | European Association of Nuclear Medicine October 20-23, 2021 Virtual |
| Publisher | Springer |
| Pages | S195-S196 |
| Number of pages | 1 |
| Volume | 48 |
| DOIs | |
| State | Published - 24 Sep 2021 |
| Event | 2021 - EANM: 34th Annual Congress of the European Association of Nuclear Medicine - Online, Barcelona Duration: 20 Oct 2021 → 23 Oct 2021 https://eanm21.eanm.org/ |
Publication series
| Name | European Journal of Nuclear Medicine and Molecular Imaging |
|---|---|
| Publisher | Springer |
| Number | Supplement Issue 1 |
| Volume | 48 |
| ISSN (Print) | 1619-7070 |
Conference
| Conference | 2021 - EANM |
|---|---|
| Country/Territory | Spain |
| City | Barcelona |
| Period | 2021-10-20 → 2021-10-23 |
| Internet address |