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

Background: Radiolabeled somatostatin analogues (e.g. [Ga-68]Ga-DOTATATE and [Lu-177]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success. [F-18]AlF-NOTA-octreotide, a promising F-18-labeled somatostatin analogue and potential alternative for Ga-68-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. (AlF)-F-18-method in combination with therapeutic radiometals Bi-213/Lu-177) 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 (AlF)-F-18-chelator and present first results of radiosynthesis and preclinical evaluation of [F-18]AlF-3p-C-N ETA-TATE. Methods: 3p-C-NETA was synthesized and radiolabeled with diagnostic (Ga-68, (AlF)-F-18) or therapeutic (Lu-177, Tb-161, Bi-213, (225)Ac( )and Cu-67) radionuclides at different temperatures (25-95 degrees 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. [F-18]AlF-3p-C-NETA-TATE was synthesized in an automated AllinOne (R) synthesis module and the in vitro stability of [F-18]AlF3p-C-NETA-TATE was evaluated in formulation buffer, PBS and human serum. [F-18]AlF-3p-C-NETA-TATE pharmacokinetics were evaluated using pPET/MRI in healthy rats, with [F-18]AlF-NOTA-Octreotide as benchmark. Results: 3p-C-NETA quantitatively sequestered Lu-177, Bi-213 and Cu-67 at 25 degrees C while heating was required to bind (AlF)-F-18, Ga-68, Tb-161 and Ac-225 efficiently. The [F-18]AlF-, [Lu-177]Lu- and [Tb-161]Tb-3p-C-NETA-complex showed excellent in vitro stability in both PBS and human serum over the study period. In contrast, [Cu-67]Cu-and [Ac-225]Ac-, [Ga-68]Ga-3p-C-NETA were stable in PBS, but not in human serum. [F-18]AlF-3p-C-NETA-TATE was obtained in good radiochemical yield and radiochemical purity. [F-18]AlF-3p-C-NETA-TATE displayed good in vitro stability for 4 h in all tested conditions. Finally, [F-18]AlF-3p-C-NETA-TATE showed excellent pharmacokinetic properties comparable with the results obtained for [F-18]AlF-NOTA-Octreotide. Conclusions: 3p-C-NETA is a versatile chelator that can be used for both diagnostic applications ((AlF)-F-18) and targeted radionuclide therapy (Bi-213, Lu-177, Tb-161). It has the potential to be the new theranostic chelator of choice for clinical applications in nuclear medicine.

Automated summary

In this study, a novel chelator 3p-C-NETA was evaluated for its potential therapeutic and diagnostic applications. [F-18]-labeled 3p-C-NETA-TATE showed good stability and pharmacokinetic properties similar to [F-18]AlF-NOTA-Octreotide, indicating its potential as a new theranostic chelator for clinical nuclear medicine applications.