Copper-64 radiopharmaceuticals for PET imaging of copper trafficking in neurological disorders

Abstract

Copper dyshomeostasis has been identified as a pathological feature of Alzheimer’s disease (AD) and Niemann-Pick disease type C1 (NPC1), as well as other neurological disorders. However, the nature of copper dysregulation in these conditions as well as its impact on disease severity and progression remain poorly understood. The growing availability of high-resolution Positron Emission Tomography (PET) systems and copper radionuclides encourages the use of copper radiotracers to measure copper fluxes in a variety of disease states with PET imaging.
In this thesis, we investigated copper trafficking at brain and whole-body levels with 64Cu-PET in preclinical models of AD and NPC1 disease. The blood-brain barrier-permeable copper-64 bis(thiosemicarbazone) complex 64Cu-GTSM was used to monitor the retention, efflux and redistribution of radiocopper within the brain, while 64Cu-acetate was used to visualise copper uptake into organs from blood plasma. In addition to these imaging studies, a new library of copper bis(thiosemicarbazone) complexes for potential use in molecular imaging applications, including measurement of copper trafficking, was generated.
64Cu-GTSM-PET revealed significant differences in 64Cu brain uptake, regional distribution and biokinetics between TASTPM transgenic AD mice and wildtype controls. Interestingly, although 64Cu-GTSM was taken up by the entire brain, the regions showing the most prominent 64Cu accumulation in TASTPM brain tissue did not coincide with the areas most affected by Aβ plaque pathology, suggesting that additional metabolic/pathological factors besides Aβ plaque deposition influence brain regional 64Cu distribution. 64Cu-acetate-PET indicated subtle but significant differences in whole-body 64Cu trafficking between TASTPM transgenic mice and healthy controls. Furthermore, 64Cu-GTSM-PET detected substantial differences in brain and blood 64Cu concentration between symptomatic NPC1 knockout mice and wildtype controls that may have added value for the diagnosis of this disorder. Taken together, these results demonstrate the potential of 64Cu-PET as a useful tool to delineate copper trafficking abnormalities associated with neurological disorders.

Date of Award	2017
Original language	English
Awarding Institution	King's College London
Supervisor	Tony Gee (Supervisor) & Philip Blower (Supervisor)