A gallium fluoride-18 complex containing a pentadentate macrocyclic ligand with a dimethylaminostilbene functional group designed for diagnostic imaging of Alzheimer's disease

Abstract

The molecular pathology of Alzheimer's disease is associated with the presence of aggregates of amyloid-β, a 39–43 amino acid peptide, that form amyloid plaques in the brain. Appropriately substituted stilbene derivatives, radiolabelled with positron-emitting radionuclides, that bind selectively to amyloid-β plaques can be used to assess plaque burden by Positron Emission Tomography (PET) imaging and assist in the diagnosis of Alzheimer's disease. In this work, a substituted pentadentate ligand based on a triazacyclononane backbone (H₂L¹) with one pendent stilbene functional group and two pendent carboxylate groups was synthesised. The new ligand binds to amyloid-β plaques present in human brain tissue. Non-conventional radiolabelling with fluorine-18 was achieved by the formation of a Ga^III-[¹⁸F]F⁻ coordinate bond to give a complex, [¹⁸F][GaL¹F]. This ligand can also be radiolabelled with gallium-68 to give [⁶⁸Ga][GaL¹F], or copper-64 to give [⁶⁴Cu][CuL¹]. The in vivo biodistribution of [¹⁸F][GaL¹F] and [⁶⁴Cu][CuL¹] was evaluated in mice, revealing that the initial uptake of [¹⁸F][GaL¹F] and [⁶⁴Cu][CuL¹] in the brain was 0.85 ± 0.13% IA g⁻¹ and 0.71 ± 0.03% IA g⁻¹ respectively. An increase in radioactivity in bone at later time points suggested that [¹⁸F][GaL¹F] is unstable in vivo.