A first-in-class dual-chelator theranostic agent designed for use with imaging-therapy radiometal pairs of different...

A covalent adduct of DFOB and DOTA separated by a l-lysine residue (DFOB-l-Lys-N ⁶-DOTA) exhibited remarkable regioselective metal binding, with {¹H}-¹³C NMR spectral shifts supporting Zr(iv) coordinating to the DFOB unit, and Lu(iii) coordinating to the DOTA unit. This first-in-class, dual-chelator theranostic design could enable the use of imaging-therapy radiometal pairs of different elements, such as ⁸⁹Zr for positron emission tomography (PET) imaging and ¹⁷⁷Lu for low-energy β^--particle radiation therapy. DFOB-l-Lys-N ⁶-DOTA was elaborated with an amine-terminated polyethylene glycol extender unit (PEG4) to give DFOB-N ²-(PEG4)-l-Lys-N ⁶-DOTA (compound D2) to enable installation of a phenyl-isothiocyanate group (Ph-NCS) for subsequent monoclonal antibody (mAb) conjugation (mAb = HuJ591). D2-mAb was radiolabeled with ⁸⁹Zr or ¹⁷⁷Lu to produce [⁸⁹Zr]Zr-D2-mAb or [¹⁷⁷Lu]Lu-D2-mAb, respectively, and in vivo PET/CT imaging and in vivo/ex vivo biodistribution properties measured with the matched controls [⁸⁹Zr]Zr-DFOB-mAb or [¹⁷⁷Lu]Lu-DOTA-mAb in a murine LNCaP prostate tumour xenograft model. The ⁸⁹Zr-immuno-PET imaging function of [⁸⁹Zr]Zr-D2-mAb and [⁸⁹Zr]Zr-DFOB-mAb showed no significant difference in tumour accumulation at 48 or 120 h post injection. [⁸⁹Zr]Zr-D2-mAb and [¹⁷⁷Lu]Lu-D2-mAb showed similar ex vivo biodistribution properties at 120 h post-injection. Tumour uptake of [¹⁷⁷Lu]Lu-D2-mAb shown by SPECT/CT imaging at 48 h and 120 h post-injection supported the therapeutic function of D2, which was corroborated by similar therapeutic efficacy between [¹⁷⁷Lu]Lu-D2-mAb and [¹⁷⁷Lu]Lu-DOTA-mAb, both showing a sustained reduction in tumour volume (>80% over 65 d) compared to vehicle. The work identifies D2 as a trifunctional chelator that could expand capabilities in mixed-element radiometal theranostics to improve dosimetry and the clinical outcomes of molecularly targeted radiation.