The Sutherland Research Group

1. Novel PET and SPECT Tracers for the Radionuclide Imaging of Disease: Many diseases are poorly diagnosed and treated due to a lack of understanding at the molecular level. One approach in gaining a better insight into disease mechanisms, is the design of non-toxic, molecular imaging agents that can bind with high affinity and high selectivity to a targeted biological receptor. The challenge is to generate functionalised molecular tracers that can produce insightful images of a specific disease. Our work has identified a number of high affinity agents that can bind with high selectivity to neurological receptors involved in dementia associated disease and cancer. In particular, a PET imaging agent has been developed that binds to the translocator protein and can be used to image brain tumours. In other work, a SPECT imaging agent has been developed that can be used to image the noradrenaline reuptake transporter in mice.


To overcome the limitations of using traditional highly toxic (organotin) methods for generating radioiodinated SPECT imaging agents, new non-toxic nickel-mediated halogen exchange reactions have been developed. More recently, iron(III) and silver(I)-catalysed methods for the mild iodination of arenes have also been reported (Org. Lett., 2015, 17, 4782; J. Org. Chem., 2016, 81, 772).

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2. Directed Overman Rearrangements and One-Pot Multi-reaction Processes for the Synthesis of Highly Functional Building Blocks and Targets: An early project developed in the group showed that methoxymethyl ethers were effective directing groups for a diastereoselective palladium(II)-catalysed Overman rearrangement. The resulting allylic anti-vicinal amino alcohol derivatives were excellent synthetic building blocks for a wide range of drug-like compounds and natural products.


More recently, our interest in rearrangements, have led to the design of new substrates that can be used in one-pot multi-reaction processes for the rapid and highly efficient synthesis of synthetic building blocks, polycyclic scaffolds and natural products. In many of these processes, it has been shown that a single transtion metal catalyst can be used to implement different transformations.


More recently, this concept has been extended to alkyne derived allylic alcohols where one-pot processes have been used, involving an Overman rearrangement, a ring closing enyne metathesis (RCEYM) reaction and a hydrogen bonding directed Diels-Alder reaction, generating polycyclic compounds with high diastereocontrol (>20:1). This has been extended to include a one-pot process involving ruthenium(II) tandem catalytic RCEYM and cross-metathesis steps, generating highly substituted amino-indanes and tetralins with up to five stereocentres (Tetrahedron, 2014, 70, 7133). The RCEYM step has also been fully investigated with disubstituted alkynes, allowing a palladium catalyst to be used for the Overman rearrangement (Org. Biomol. Chem., 2016, 14, 3284).

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3. Use of Enone Derived Amino Acids for the Synthesis of Piperidine Targets and Fluorescent Imaging Agents: We have a general interest in the novel and efficient synthesis of amino acids of particular biological importance. For a number of years, we have been exploring the chemical and biological applications of enone derived amino acids. We have shown that these compounds can undergo 6-endo-trig cyclisations to form pipecolic acids. The stereochemical outcome of these reactions can be switched depending on the level of substitution on the amine. Enone derived amino acids are also being explored as substrates for heterocyclisations and as fluorescent probes for biological imaging (Org. Biomol. Chem., 2009, 7, 4309; Org. Biomol. Chem., 2015, 13, 4514).

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Acknowledgements: We are grateful to the following organisations for their financial support of our work.