AAZTA(5)/AAZTA(5)-TOC: synthesis and radiochemical evaluation with (68)Ga, (44)Sc and (177)Lu

PURPOSE: AAZTA (1,4-bis (carboxymethyl)-6-[bis (carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) based chelators were initially developed in the context of magnetic resonance imaging. First radiochemical studies showed the capability of AAZTA to form stable complexes with radiolanthanides and moderately stable complexes with (68)Ga. For a systematic comparison of the labelling capabilities with current diagnostic and therapeutic trivalent radiometals, AAZTA(5) (1,4-bis (carboxymethyl)-6-[bis (carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine) was synthesized representing a bifunctional version with a pentanoic acid at the carbon-6 atom. To evaluate the effect of adding a targeting vector (TV) to the bifunctional chelator on the complex formation, AAZTA(5)-TOC was synthesized, radiolabeled and tested in comparison to the uncoupled AAZTA(5). METHODS: AAZTA(5) was synthesized in a 5-step synthesis. It was coupled to the cyclic peptide TOC (Phe(1)-Tyr(3) octreotide) via amide bound formation. AAZTA and AAZTA(5)-TOC complex formations with (68)Ga, (44)Sc and (177)Lu were investigated at different pH, temperature and precursor amounts. Stability studies against human serum, PBS buffer, EDTA and DTPA were performed. RESULTS: AAZTA(5) and AAZTA(5)-TOC achieved quantitative labelling (> 95%) at room temperature in less than 5 min with all three nuclides at pH ranges from 4 to 5.5 with low precursor amounts of 1 to 10 nmol. [(44)Sc]Sc-AAZTA(5) complexes as well as [(44)Sc]Sc-AAZTA(5)-TOC were completely stable. The (177)Lu complexes of AAZTA(5) and AAZTA(5)-TOC showed high stability comparable to the (44)Sc complexes. In contrast, the [(68)Ga]Ga-AAZTA(5) complex stability was rather low, but interestingly, [(68)Ga]Ga-AAZTA(5)-TOC was completely stable. CONCLUSION: AAZTA(5) appears to be a promising bifunctional chelator for (68)Ga, (44)Sc and (177)Lu with outstanding labelling capabilities at room temperature. Complex stabilities are high in the case of (44)Sc and (177)Lu. While [(68)Ga]Ga-AAZTA complexes alone lacking stability, [(68)Ga]Ga-AAZTA(5)-TOC demonstrated high stability. The latter indicates an interesting feature of [(68)Ga]Ga-AAZTA(5)–labelled radiopharmaceuticals.