title: Ligand Specific Efficiency (LSE) Index for PET Tracer Optimization.
abstract: 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 nonspecific binding (NSB) to membranes and non-target proteins 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 for quantification of binding affinity to the target of interest, relative to NSB. Its use was illustrated by the optimization of PET tracer candidates for the prostacyclin receptor.
authors.affiliation: Novartis Institutes for BioMedical Research, Klybeckstrasse 141, 4057, Basel, Switzerland. yves.auberson@novartis.com.
authors.forename: Yves P
authors.identifier: 0000-0001-5800-4811
authors.initials: YP
authors.lastname: Auberson
authors.affiliation: Novartis Institutes for BioMedical Research, Klybeckstrasse 141, 4057, Basel, Switzerland.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Briard
authors.affiliation: University of Nottingham, Cell Signalling Department, Nottingham, NG7 2RD, UK.
authors.forename: David
authors.initials: D
authors.lastname: Sykes
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: John
authors.initials: J
authors.lastname: Reilly
authors.affiliation: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Healy
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D003412:Cricetulus; D004174:Diprenorphine / Q000737:chemistry / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008567:Membranes, Artificial; D009292:Narcotic Antagonists / Q000737:chemistry / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000494:pharmacology; D044006:Receptors, Epoprostenol / Q000737:chemistry / Q000378:metabolism; D014316:Tritium
chemical_list: D000814:Aniline Compounds; D001549:Benzamides; D065127:Dopamine D2 Receptor Antagonists; D007093:Imidazoles; D008024:Ligands; D008567:Membranes, Artificial; D009292:Narcotic Antagonists; C113936:PTGIR protein, human; D011728:Pyridones; D019275:Radiopharmaceuticals; D044006:Receptors, Epoprostenol; C000622556:Ro 1138452; D014316:Tritium; D004174:Diprenorphine; C574003:fallypride
keywords: imaging agents; inhibitor design; ligand efficiency; medicinal chemistry; prostacyclin receptor