Determing structure-activity relationships between novel pet radiotracers and their non-specific binding properties

Chloe Rose Child, GlaxoSmithKline ; Biotechnology And Biological Sciences Research Council (Great Britain), Tony Gee, Nicholas Long
2012
The non-invasive imaging modality positron emission tomography (PET) is used extensively in clinical settings and is increasingly being used by the pharmaceutical industry in drug development. Molecules of biological interest are labelled with positron emitting isotopes e.g. 11C, allowing their biodistribution and kinetics to be followed in vivo. A major factor in the failure of radioligands is the magnitude of unwanted background signal, non-specific binding (NSB) obscuring binding to the
more » ... binding to the desired target. Assumptions have previously been made as to the physiochemical and pharmacological properties of radioligands that can affect NSB. However, little work has been carried out to quantify NSB with regard to determining structure-activity relationships (SARs) in order to optimise efficient radiotracer discovery. Non-specific binding is a poorly understood process but is believed to be related to the non-saturable binding of labelled molecules with tissue membranes. In this work the synthesis of novel radiolabelled molecular libraries has been conducted, their physicochemical properties determined and their non-specific binding measured in vitro using autoradiographical and cell based mass spectrometry assay methods. Structure-activity relationships have been formed between partition coefficient properties, acid dissociation constants, interaction energies and molecular weight in order to determine the effect each of these properties has on non-specific binding. Traditionally lipophilicity, log P, of a radioligand is the main predictor to its non-specific binding properties. However from this work it has been shown that a single physicochemical property cannot be relied on to predict the NSB of a radioligand but multiple properties must be considered.
doi:10.25560/9576 fatcat:ddtrlx2ctfg2vginhv2onhqfom