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

Abstract

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.

Peptide-based positron emission tomography probes: current strategies for synthesis and radiolabelling

“…[ 18 F]AlF-NOTA-Octreotide and [ 18 F]AlF-FAPI-74 are some excellent examples of this promising development. [21][22][23] Recently, Ahenkorah et al 24 found an alternative to NOTA as Al 18 Fchelator that can also be used in combination with therapeutic radionuclides ( 177 Lu, 161 Tb, 213 Bi, 225 Ac and 67 Cu), and has superior labelling kinetics over DOTA. 3p-C-NETA ({4-[2-(bis-carboxy-methylamino)-5-(4-nitrophenyl)-entyl]-7-carboxymethyl-[1, 4,7]tri-azonan-1-yl} acetic acid), a ligand bearing both a parent macrocyclic NODA (1,4,7-triazacyclononane-N,N'-diacetic acid) backbone and a flexible acyclic tridentate pendant arm, has been reported by Chong et al to be a promising chelator in terms of kinetics and stability for βemitters, such as 90 Y and 177 Lu.…”

“…[ 18 F]AlF-NOTA-octreotide and [ 18 F]AlF-FAPI-74 are some excellent examples of this promising development. [21][22][23] Recently, Ahenkorah et al 24 found an alternative to NOTA as Al 18 F-chelator that can also be used in combination with therapeutic radionuclides ( 177 Lu, 161 Tb, 213 Bi, 225 90 Y and 177 Lu. [25][26][27] As 3p-C-NETA also contains a NODA backbone, Ahenkorah and coworkers 24 assumed that it might be a suitable chelator for Al 18 F-chelation and thus could be a good theranostic chelator for 18 F and therapeutic radionuclides.…”

“…[21][22][23] Recently, Ahenkorah et al 24 found an alternative to NOTA as Al 18 F-chelator that can also be used in combination with therapeutic radionuclides ( 177 Lu, 161 Tb, 213 Bi, 225 90 Y and 177 Lu. [25][26][27] As 3p-C-NETA also contains a NODA backbone, Ahenkorah and coworkers 24 assumed that it might be a suitable chelator for Al 18 F-chelation and thus could be a good theranostic chelator for 18 F and therapeutic radionuclides. They synthesised the 3p-C-NETA, based on a published method developed by Kang et al, 28 and its new bifunctional derivative 3p-C-NETA-(tBu)oxa-butanoic acid.…”

“…3p- C -NETA ({4-[2-(bis-carboxy-methylamino)-5-(4-nitrophenyl)-entyl]-7-carboxymethyl-[1,4,7]tri-azonan-1-yl}acetic acid), a ligand bearing both a parent macrocyclic NODA (1,4,7-triazacyclononane- N , N ′-diacetic acid) backbone and a flexible acyclic tridentate pendant arm, has been reported by Chong et al to be a promising chelator in terms of kinetics and stability for β − emitters, such as 90 Y and 177 Lu. 25–27 As 3p- C -NETA also contains a NODA backbone, Ahenkorah and co-workers 24 assumed that it might be a suitable chelator for Al 18 F-chelation and thus could be a good theranostic chelator for 18 F and therapeutic radionuclides. They synthesised the 3p- C -NETA, based on a published method developed by Kang et al , 28 and its new bifunctional derivative 3p- C -NETA-( t Bu)-oxa-butanoic acid.…”

Optimizing the Safety and Efficacy of Bio-Radiopharmaceuticals for Cancer Therapy

“…Additionally, only one GMP-grade pre-functionalized vector needs to be developed and produced, resulting in lower costs and reduced development time. An example is the novel 3p-C-NETA chelator, which is reported to have both acyclic and cyclic chelator characteristics [ 104 ]. The cyclic components provide thermodynamic stability and rigidity to the complex, while the acyclic components of NETA can accelerate the complexation process.…”