Comparative gallium-68 labeling of TRAP-, NOTA-, and DOTA-peptides: practical consequences for the future of gallium-68-PET

Background: Currently, Ga-68-labeled 1,4,7,10-tetraazacyclododecane-tetraacetic acid (DOTA)-peptides are the most widely used class of Ga-68 radiotracers for PET, although DOTA is not optimal for Ga-68 complexation. More recently, 1,4,7-triazacyclononane-triacetic acid (NOTA) and particularly triazacyclononane-phosphinate (TRAP) chelators have been shown to possess superior Ga-68 binding ability. Here, we report on the efficiency, reproducibility, and achievable specific activity for fully automated Ga-68 labeling of DOTA-, NOTA-, and TRAP-peptide conjugates. Findings: Compared to NOTA- and DOTA-peptides, achievable specific activity (A(S)) for TRAP-peptide is approximately 10 and 20 times higher, respectively. A(S) values in the range of 5,000 GBq/mu mol were routinely obtained using 1 GBq of Ga-68, equivalent to 0.11 mu g of cold mass for a 185-MBq patient dose of a 3-kDa conjugate. The TRAP-peptide could be Ga-68-labeled with excellent reproducibility and >95% radiochemical yield for precursor amounts as low as 1 nmol. Conclusions: High Ga-68 labeling efficiency of TRAP-peptides could facilitate realization of kit labeling procedures. The good reproducibility of the automated synthesis is of relevance for GMP production, and the possibility to provide very high specific activities offers a high degree of safety in first clinical trials, due to reduction of cold mass content in tracer formulations.