Yttrium macrocycles and their use in the treatment of cancer

Six macrocyclic ligands have been synthesized for binding yttrium(III). Of the six, 1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (DOTA) forms the most stable yttrium(III) complex in aqueous solution, log K(ML) = 24.9 and half life ~ 2 weeks at pH 1.0. In addition to an acid-dependent dissociative mechanism, release of Y(^3+) from Y(DOTA) may, it is tentatively suggested, be promoted by metal ions. DOTA also demonstrates rapid uptake of Y(^3+) (98% labelling efficiency at 310 K with [DOTA] = 10(^-5) M and [Y(^3+)1 ~ 10(^-9) M, pH 5.5 [0.1 M ammonium acetate]). Accordingly, an aminobutyl C-functionalised derivative of DOTA has been made and coupled to a monoclonal antibody. Once labelled with (^90)Y(^3+) a long range β- emitter, the conjugate can be used to selectively deliver a sterilising dose of radiation to a tumour. Preliminary experiments have indicated that the radiolabelled MoAb conjugate remains relatively inert in vivo. Tumour regression studies are in progress.