The Ligand Specific Efficiency (LSE) index for PET tracer optimization, illustrated with tracer candidates for imaging the prostacyclin receptor.

Ligand efficiency indices are widely used to guide chemical optimization in drug discovery, due to their predictive value in the early steps of optimization. At later stages however, as more complex properties become critical for success, indices relying on calculated, rather than experimental parameters become less informative. This problem is particularly acute when developing positron emission tomography (PET) imaging agents, for which non-specific binding to membranes (NSB) is a frequent cause of failure. NSB cannot be predicted using in silico parameters. To address this gap, we explored the use of the experimentally determined chromatographic hydrophobicity index on immobilized artificial membranes, CHI(IAM), to guide the optimization of NSB. The Ligand Specific Efficiency (LSE) index was defined as the ratio between affinity (pIC50 or pKd), and the logarithmic value of CHI(IAM). It allows the quantification of binding affinity to the target of interest relative to non-specific binding. Its use is illustrated with the optimization of PET tracer candidates for the prostacyclin receptor