Positron emission tomography imaging agents with gallium-68 : bifunctional chelators and multimodality

Positron emission tomography (PET) as a nuclear medicine technique offers very high sensitivity compared with other imaging modalities. PET is often combined with computed tomography (CT) to offer structural information. Incorporation of a positron emitting metal radioisotope such as 68Ga requires a bifunctional chelator (BFC) to form a stable complex in vivo and for covalent bond formation (conjugation) with a targeting moiety. In this work, the routinely used macrocyclic BFC DOTA has been modified to replace an acetate arm with a benzimidazole unit to give an alternative BFC structure. It does not affect coordination number, has a secondary amine for bioconjugation and is a chromophore, therefore increasing the number of potential applications beyond DOTA to include optical properties (fluorescence and lanthanide luminescence sensitisation). Four benzimidazole DO3A derivatives have been synthesised and radiolabelled with 68Ga in comparable radiochemical yields to the structurally similar DOTA. Reaction conditions of ca. 5 minutes at room temperature are shorter and milder than those required for DOTA, which can cause degradation of conjugated biomolecules.Magnetic resonance imaging (MRI) can replace CT as the structural partner in clinical PET imaging and has many advantages including the potential for use of MRI contrast agents. PET/MRI is an emerging field and there is scope for the development of multimodal imaging constructs combining a PET radioisotope with a MRI contrast agent. In this work, super-paramagnetic iron oxide nanoparticles (SPIONs) as T2 MRI contrast agents have been functionalised with a range of macrocyclic derivatives and radiolabelled with 68Ga in near quantitative yields to form PET/MRI multi-modal imaging agents which have been shown to be stable to EDTA competition and in serum over four hours. Modification of the surface of the SPIONs was shown to have no detrimental effect to their clinical applicability by size variation (aggregation).The use of the chelators synthesised in the work for other applications is also of interest, with preliminary studies carried out towards the development of 86Y and 90Y agents for PET and radioimmunotherapy respectively. Benzimidazole DO3A, along with the corresponding yttrium(III) and europium(III) complexes were studied by potentiometric titration, luminescent lifetime measurements and variable temperature NMR to fully characterise the coordination sphere and gain insight into their physicochemical characteristics