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

Abstract

<b>Background</b>: Radiolabeled somatostatin analogues (<i>e.g.</i> [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 (<i>e.g.</i> Al¹⁸F-method in combination with therapeutic radiometals ²¹³Bi/¹⁷⁷Lu) or identical (<i>e.g.</i> complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients. In this study we evaluated 3p-<i>C</i>-NETA, as potential theranostic Al¹⁸F-chelator and present first results of radiosynthesis and preclinical evaluation of [¹⁸F]AlF-3p-<i>C</i>-NETA-TATE. <b>Methods</b>: 3p-<i>C</i>-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 <i>in vitro</i> stability of the corresponding radiocomplexes was determined in phosphate-buffered saline (PBS) and human serum. 3p-<i>C</i>-NETA-TATE was synthesized using standard solid/liquid-phase peptide synthesis. [¹⁸F]AlF-3p-<i>C</i>-NETA-TATE was synthesized in an automated AllinOne® synthesis module and the <i>in vitro</i> stability of [¹⁸F]AlF-3p-<i>C</i>-NETA-TATE was evaluated in formulation buffer, PBS and human serum. [¹⁸F]AlF-3p-<i>C</i>-NETA-TATE pharmacokinetics were evaluated using µPET/MRI in healthy rats, with [¹⁸F]AlF-NOTA-Octreotide as benchmark. <b>Results</b>: 3p-<i>C</i>-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-<i>C</i>-NETA-complex showed excellent <i>in vitro</i> stability in both PBS and human serum over the study period. In contrast, [⁶⁷Cu]Cu- and [²²⁵Ac]Ac-, [⁶⁸Ga]Ga-3p-<i>C</i>-NETA were stable in PBS, but not in human serum. [¹⁸F]AlF-3p-<i>C</i>-NETA-TATE was obtained in good radiochemical yield and radiochemical purity. [¹⁸F]AlF-3p-<i>C</i>-NETA-TATE displayed good <i>in vitro</i> stability for 4 h in all tested conditions. Finally, [¹⁸F]AlF-3p-<i>C</i>-NETA-TATE showed excellent pharmacokinetic properties comparable with the results obtained for [¹⁸F]AlF-NOTA-Octreotide. <b>Conclusions</b>: 3p-<i>C</i>-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.