3p-C-NETA: A Versatile Theranostic Chelator Platform Enabling Al18F- and 177Lu-Labeled SSTR2-Targeted Radioligands

Background/Objectives: The FDA and EMA approvals of the theranostic radiopharmaceuticals [68Ga]Ga-/[177Lu]Lu-DOTA-TATE represent milestones in SSTR2-targeted radioligand development. The use of a single precursor for both diagnostic and therapeutic applications facilitates the development of matched theranostic agents. However, the DOTA chelator is not compatible with fluorine-18 (Al18F) labeling, which offers advantages in terms of imaging quality and clinical logistics. Here, we evaluated 3p-C-NETA-TATE, a precursor capable of incorporating either Al18F or lutetium-177, building on previous work establishing 3p-C-NETA as a versatile theranostic chelator platform. Methods: The precursor 3p-C-NETA-TATE was labeled with Al18F or lutetium-177, and both compounds were evaluated in a preclinical setting. Both radioligands were assessed in vitro (binding affinity) and ex vivo (biodistribution) to determine their equivalent biological behavior. [177Lu]Lu-3p-C-NETA-TATE was compared with [177Lu]Lu-DOTA-TATE in terms of labeling efficiency, stability and cytotoxicity. Additionally, [18F]AlF-3p-C-NETA-TATE was used in a PET imaging study with tumor-bearing mice. Results: [177Lu]Lu-3p-C-NETA-TATE was obtained in quantitative radiolabeling yields (>95%) at a lower temperature and precursor concentration compared with [177Lu]Lu-DOTA-TATE, albeit with reduced stability in serum. In vitro, [177Lu]Lu-3p-C-NETA-TATE demonstrated comparable or improved characteristics. Both in vitro affinity experiments and ex vivo biodistribution studies indicated a similar biological profile for [18F]AlF-/[177Lu]Lu-3p-C-NETA-TATE. Conclusions: This study demonstrates the theranostic potential of the 3p-C-NETA platform using TATE as a model targeting vector. The ability to support both Al18F and lutetium-177 labeling, combined with the comparable biological behavior of the resulting radioligands, highlights its potential as a versatile platform for the development of next-generation diagnostic and therapeutic radiopharmaceuticals.