| Summary: | Positron emission tomography (PET) is used for non-invasive high sensitivity molecular imaging to diagnose diseases, to follow biological processes or to monitor treatment response. Immuno-PET is an imaging technique used to improve the visualisation of a target site by combining the high sensitivity of PET with the specificity of monoclonal antibodies (mAbs). Due to the relatively slow pharmacokinetics of antibodies, the half-life of the radioisotope and the stability of radioisotope attachment are key factors in the development of immuno-PET imaging agents. Zirconium-89 is an excellent candidate to be the immuno-PET radionuclide of choice as it decays with a half-life of 78.41 hours. DFO (acyclic structure) is the most common chelator used to bind to [89Zr]Zr(IV) for imaging applications. However, it has been reported that the [89Zr]ZrDFO-mAb conjugate showed decomplexation and significant uptake of radioactivity in bones. The bone uptake of free [89Zr]Zr(IV) results in increased radiation dose to the bone marrow and a decrease in target-to-background ratio. Therefore, the development of a more suitable chelator for [89Zr]Zr(IV) is of high interest to biomedical researchers. The tetraazamacrocycle cyclen was functionalised with three different pendant arms; phosphonic acid, phosphinic acid and picolinic acid, to offer at least eight binding sites for Zr(IV) to form complexes with the metal ion either “in cavity” or “out of cavity”. A preliminary study of [89Zr]Zr(IV) radiolabelling of compounds 1, 5 and 9 was performed in acetate buffer at pH 7, with [89Zr]zirconium(IV) oxalate incubated at 95oC for 2 hours to obtain 5.0%, 6.1% and 8.4% labelling yields respectively. Labelling with [89Zr]zirconium(IV) chloride was performed either in water or acetate buffer to form [89Zr]Zr9 in a 49.3% labelling yield when using 0.5 MBq of [89Zr]Zr(IV) in 0.2 M acetate buffer at pH 6 incubated at 95oC for 2 hours but achieving this yield required a higher concentration of the chelator. Extended picolinic acid arm chelators were synthesised with both cyclen and cyclam backbones. Compounds 16 and 20 were synthesised and labelled with [89Zr]zirconium(IV) chloride. Unexpectedly [89Zr]Zr9 gives higher radiolabelling yields than [89Zr]Zr16 and [89Zr]Zr20. It was possible that 16 and 20 formed lower stability complexes with Zr(IV) with a higher chelator to metal ratio than the anticipated 1:1 ratio, and so the chelators are not octadentate. Novel macrocycle-linked DFO chelators were designed as the linear chelator DFO rapidly forms a complex with Zr(IV) at ambient temperature and then the metal could transfer to the cyclic ring giving a higher stability thermodynamic product (the “in-cavity” complex). Compounds 21, 22 and 23 were synthesized and labelled with [89Zr]Zr(IV). The labelled compounds were stable in 100-fold excess EDTA and fetal bovine serum but did not show any clear improvement over DFO.
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