Label-free assay for the assessment of nonspecific binding of positron emission tomography tracer candidates

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Frauke AssmusHolger Fischer

Abstract

Positron emission tomography (PET) is a valuable non-invasive technique for the visualization of drug tissue distribution and receptor occupancy at the target site in living animals and men. Many potential PET tracers, however, fail due to an unfavorably high non-specific binding (NSB) to non-target proteins and phospholipid membranes which compromises the sensitivity of PET. Hence, there is a high demand to assess the extent of NSB as early as possible in the PET tracer development process, preferentially before ligands are radiolabeled and elaborate imaging studies are performed. The purpose of this study was to establish a novel Lipid Membrane Binding Assay (LIMBA) for assessing the tendency of potential tracers to bind non-specifically to brain tissue. The assay works with unlabeled compounds and allows the medium-throughput measurement of brain tissue/water distribution coefficients, logDbrain (pH7.4), at minimal expense of animal tissue. To validate LIMBA, logDbrain (pH7.4) values were measured and compared with NSB estimates derived from in vivo PET studies in human brain (n=10 tracers, literature data), and in vitro autoradiography studies in rat and mouse brain slices (n=30 tritiated radioligands). Good agreement betwe...Continue Reading

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Citations

May 20, 2016·ChemMedChem·Yves P AubersonMark Healy
Apr 28, 2021·Journal of Medicinal Chemistry·Yuta Takamura, Hiroki Kakuta
Jun 27, 2021·Nuclear Medicine and Biology·Berend van der WildtFrederick T Chin

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