Full Text | PDF

Theranostics 2022; 12(13):5971-5985. doi:10.7150/thno.75336 This issue Cite

Research Paper

3p-C-NETA: A versatile and effective chelator for development of Al¹⁸F-labeled and therapeutic radiopharmaceuticals

Stephen Ahenkorah^1,2, Erika Murce³, Christopher Cawthorne⁴, Jessica Pougoue Ketchemen⁵, Christophe M. Deroose⁴, Thomas Cardinaels^1,6, Yann Seimbille^3,7, Humphrey Fonge^5,8, Willy Gsell⁹, Guy Bormans², Maarten Ooms^1✉, Frederik Cleeren^2✉

1. NURA, Belgian Nuclear Research Center (SCK CEN), Mol, Belgium.
2. Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological sciences, University of Leuven, Leuven, Belgium.
3. Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands.
4. Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
5. Department of Medical Imaging, College of Medicine, University of Saskatchewan, Saskatoon, Canada.
6. Department of Chemistry, University of Leuven, Leuven, Belgium.
7. Life Sciences Division, TRIUMF, Vancouver, Canada.
8. Department of Medical Imaging, Royal University Hospital (RUH), Saskatoon, Canada.
9. Biomedical MRI/MoSAIC, Department of Imaging and Pathology, Biomedical Sciences Group, University of Leuven, Leuven, Belgium.

✉ Corresponding authors: E-mail: maarten.oomsbe (M.O) and frederik.cleerenbe (F.C); Phone: +32 14333283 (M.O) and +32 16377237 (F.C).

Abstract

Background: Radiolabeled somatostatin analogues (e.g. [⁶⁸Ga]Ga-DOTATATE and [¹⁷⁷Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success. [¹⁸F]AlF-NOTA-octreotide, a promising ¹⁸F-labeled somatostatin analogue and potential alternative for ⁶⁸Ga-DOTA-peptides, is under clinical evaluation. However, ideally, the same precursor (combination of chelator-linker-vector) can be used for production of both diagnostic and therapeutic radiopharmaceuticals with very similar (e.g. Al¹⁸F-method in combination with therapeutic radiometals ²¹³Bi/¹⁷⁷Lu) or identical (e.g. complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients. In this study we evaluated 3p-C-NETA, as potential theranostic Al¹⁸F-chelator and present first results of radiosynthesis and preclinical evaluation of [¹⁸F]AlF-3p-C-NETA-TATE.

Methods: 3p-C-NETA was synthesized and radiolabeled with diagnostic (⁶⁸Ga, Al¹⁸F) or therapeutic (¹⁷⁷Lu, ¹⁶¹Tb, ²¹³Bi, ²²⁵Ac and ⁶⁷Cu) radionuclides at different temperatures (25-95 °C). The in vitro stability of the corresponding radiocomplexes was determined in phosphate-buffered saline (PBS) and human serum. 3p-C-NETA-TATE was synthesized using standard solid/liquid-phase peptide synthesis. [¹⁸F]AlF-3p-C-NETA-TATE was synthesized in an automated AllinOne® synthesis module and the in vitro stability of [¹⁸F]AlF-3p-C-NETA-TATE was evaluated in formulation buffer, PBS and human serum. [¹⁸F]AlF-3p-C-NETA-TATE pharmacokinetics were evaluated using µPET/MRI in healthy rats, with [¹⁸F]AlF-NOTA-Octreotide as benchmark.

Results: 3p-C-NETA quantitatively sequestered ¹⁷⁷Lu, ²¹³Bi and ⁶⁷Cu at 25 °C while heating was required to bind Al¹⁸F, ⁶⁸Ga, ¹⁶¹Tb and ²²⁵Ac efficiently. The [¹⁸F]AlF-, [¹⁷⁷Lu]Lu- and [¹⁶¹Tb]Tb-3p-C-NETA-complex showed excellent in vitro stability in both PBS and human serum over the study period. In contrast, [⁶⁷Cu]Cu- and [²²⁵Ac]Ac-, [⁶⁸Ga]Ga-3p-C-NETA were stable in PBS, but not in human serum. [¹⁸F]AlF-3p-C-NETA-TATE was obtained in good radiochemical yield and radiochemical purity. [¹⁸F]AlF-3p-C-NETA-TATE displayed good in vitro stability for 4 h in all tested conditions. Finally, [¹⁸F]AlF-3p-C-NETA-TATE showed excellent pharmacokinetic properties comparable with the results obtained for [¹⁸F]AlF-NOTA-Octreotide.

Conclusions: 3p-C-NETA is a versatile chelator that can be used for both diagnostic applications (Al¹⁸F) and targeted radionuclide therapy (²¹³Bi, ¹⁷⁷Lu, ¹⁶¹Tb). It has the potential to be the new theranostic chelator of choice for clinical applications in nuclear medicine.

Keywords: 3p-C-NETA, Al¹⁸F, PET, targeted radionuclide therapy, radiopharmaceutical

Citation styles

©2024 Ivyspring International Publisher. Terms of use