Studies of drug-lipid interactions

Positron emission tomography (PET) is increasingly being used by the pharmaceutical industry in drug development. Drugs are designed to bind to a specific target, which is usually a membrane embedded receptor or an enzyme. PET is used to establish the utility of radiolabelled drugs and other radioligands in vivo before embarking on expensive clinical trials. In developing new PET radioligands, a common reason for candidate rejection is that the non-specific binding signal obscures the specific binding signal and, thus reduces the quality of the PET scan data. A high non-specific/specific binding ratio is a major reason for radiotracer failure and there is no completely satisfactory predictor of its magnitude. Non-specific binding is a poorly understood phenomenon but is believed to be related to the binding of labelled molecules to tissue membranes. A series of Spiperone analogues have been synthesised and tested in a variety of biophysical assays to increase the understanding of the molecular basis of drug-lipid interactions. Rapid cyclic voltammetry experiments were also performed to examine the interaction of drugs with a DOPC monolayer on a Pt/Hg electrode. The Spiperone analogues were tested in this system and the larger molecules were shown to have a larger interaction with the DOPC monolayer. A set of well characterised central nervous system drugs were also tested in this system and it was found that the strength of their interaction has a strong correlation with the measured in vivo non-specific binding. This technique could therefore be used to screen candidate drugs and radioligands to predict their non-specific binding. An assay that can select compounds that display the greatest likelihood of success would be extremely valuable due to the high cost and low-throughput nature of PET imaging.