1st supervisor: Nick Long
2nd supervisor: Rick Southworth
Apoptosis is the most common form of programmed cell death and is found to be the key mechanism in many pathological diseases. These include cancer, diabetes, neurodegenerative disorders and also general aging. Being able to fully understand this mechanism could lead to huge advances in detection, drug development and treatment. Currently there are very few non-invasive techniques with which to quantify and assess the process of apoptosis in humans. The discovery that the mitochondria play an important role in the early stages of apoptosis and therefore its dysfunction can be directly related to these pathologies has directed focus to targeting the mitochondria. Evidence has shown that alterations to the inner membrane potential of the mitochondria can be directly related to the organelles dysfunction and therefore present a potential process to image. For instance, carcinoma cells exert a higher membrane potential and therefore compounds such as lipophilic cations can selectively accumulate in cancer cells over healthy cells.
Positron Emission Tomography (PET) is a non-invasive imaging approach that allows the visualisation and quantification of biological processes at a molecular level. Lipophilic cations, which as stated above accumulate in mitochondria due to the electrochemical membrane potential, provide a potential target for novel PET probe development. Indeed, recent developments with F-18 and Tc-99m support the application of labelled lipophilic cations e.g. as imaging probes of apoptosis in oncology (Appl. Rad. Isot., 68, 2010, 96; J. Nucl. Med., 50, 2009, 774). Recently, the Long group have developed a series of new F-18 labelled phosphonium cations and tested their ability to act as apoptosis imaging agents in in vitro models and preclinical studies (J. Label. Compd. Radiopharm., 56, 2013, 313). To date, there have just been one or two isolated examples of Ga-68 PET tracers being investigated within the lipophilic cation strategy (J. Nucl. Med., 46, 2005, 354), and the proposed project will address this via new ligand design and metal coordination chemistry. The availability of Ga-68 from in-house modern Ge-68/Ga-68 generators, independent of an on-site cyclotron, has made this isotope an attractive alternative to F-18 radiolabelling. Its half-life, of around 68 mins, makes it ideal from a chemistry point of view, as 2 or 3 elutions can be performed per day (with 3-5 hours separation between each elution). The key challenge is the design of new and stable ligands for the gallium centre that maintain an overall positive (cationic) charge following complexation.
Coupled with new metal-ligand coordination chemistry, the project will involve rigorous evaluation of the probes in a biomedical setting i.e. via a perfused, isolated heart model. There are other factors apart from mitochondria that can affect uptake/retention so the project will examine other ways of eliminating these e.g. multidrug resistance transporters and perfusion/blood flow, by using multimodality imaging or dynamic scanning to study kinetics.