AAZTA-5: a new kit-type chelator for Lu-177 and Sc-44 with theranostic application in conjunction with DATA-5m for Ga-68

Objectives Chelators for theranostic application provide access to tracers for imaging and therapy. The main representative is DOTA, whose conjuagtes like DOTA-TOC however are labeled under harsh conditions. The aim of this work was the development of a chelator and it’s TOC-derivative, that is capable of kit-type labeling (RT, pH 4.5-5.5). Both should be evaluated with Lu-177 as well as Sc-44 among kit-type labeling conditions.

Methods The bifunctional chelator AAZTA-5 (6-Amino-6-(5-methoxy-5-oxopentyl)-1,4-diacepine-tetraacetate) was synthesized in a 5-step synthesis and further coupled with TOC in 3 steps. Both derivatives were characterized and labeled at room temperature with Lu-177, Sc-44 and Ga-68 varying pH, time and chelator concentration. Complex stabilities against PBS-buffer, human serum, DTPA and EDTA were tested and challenge studies against iron were performed. For comparison analog experiments were performed with the bifunctional chelator DATA-5m (6-Methylamino-6-(5-methoxy-5-oxopentyl)-1,4-diacepine-triacetate) for Ga-68 and with a DOTA analog (5-methoxy-5-oxopentyl-DO3A) with Lu-177, Sc-44 and Ga-68.

Results Labeling studies of AAZTA-5 and AAZTA-5-TOC with all 3 radiometals showed quantitative yields at room temperature within minutes (< 5 min), whereas the DOTA derivative couldn’t reach these results with Lu-177 and Sc-44 below 90 °C (< 10 min). Increasing stability of the complexes was found in the order Ga < Lu < Sc, respectively. Ga-68-DATA-5m and Ga-68-DATA-5m-TOC as well showed quantitative labeling yields greater 95 % after 3 min and maximum stabilities (over 90 % (intact complex) after 120 min in all media).

Conclusions The bifunctional chelator AAZTA-5 is able of complexing Sc-44, Ga-68 and Lu-177. In a proof-of-principle study AAZTA-5 showed the capability of adding a targeting vector to the binding side without losing the ability of kit-type labeling. AAZTA-5 and AAZTA-5-TOC showed quanititative labeling under mild conditions as well as high complex stabilities. Especially the stability for Sc-44 seems to be resilient enough for in vivo application. The AAZTA-5 is suitable forming a chelator couple with the DATA-5m, which opens a wide spectrum for the theranostics through kit-type labeling.