Stability Estimation of Gallium Complexes of DOTA Derivatives for Radiotheranostic Applications

1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic
acid (DO3A)
has
been used to prepare 68Ga-labeled probes for the diagnostic
counterpart of radiotheranostic applications. While DO3A provides
stable complexes with therapeutic radionuclides such as 90Y, 177Lu, and 225Ac, further improvement of
the in vivo stability of the Ga-DO3A complex is required.
Considering the high stability of an intact Ga-DOTA complex, the stability
of Ga complexes of DOTA and DO3A derivatives, including benzyl-DOTA
(Bn-DOTA), was evaluated to gain fundamental knowledge for developing
the next-generation radiotheranostic probes using 68Ga
as a diagnostic counterpart. Following the complexation reaction to
prepare 67Ga-labeled DOTA and DO3A derivatives, the stability
of the resulting 67Ga-labeled compounds was evaluated in
murine plasma and apo-transferrin challenge. [67Ga]Ga-Bn-DOTA
produced two isomers, and one of the isomers exhibited the highest
stability among the tested complexes. The X-ray crystallography showed
that the less stable isomer of Ga-Bn-DOTA suggested an N3O3 coordination geometry, while Ga-DOTA and Ga-Bn-DO3A
show N4O2 coordination. To further evaluate
the stability, a synthetic somatostatin analogue, [Tyr3]octreotide (TOC), was used as a model peptide, and p-COOH-Bn-DOTA and DO3A were conjugated with TOC to prepare DOTA-Bn-TOC
and DOTATOC. [67Ga]Ga-DOTA-Bn-TOC also yielded two isomers
with varying stability, and one isomer exhibited significantly higher
stability than [67Ga]Ga-DOTATOC both in vitro and in vivo. These findings indicate that para-substituted Bn-DOTA would constitute a suitable chelating
agent for developing next-generation radiotheranostic probes, although
high-performance liquid chromatography purification is needed. Thus,
further chemical modification on the Bn-DOTA molecule is also needed
to avoid the formation of a Ga complex with the N3O3 configuration.