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

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