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

Assmus, Frauke and Seelig, Anna and Gobbi, Luca and Borroni, Edilio and Glaentzlin, Patricia and Fischer, Holger. (2015) Label-free assay for the assessment of nonspecific binding of positron emission tomography tracer candidates. European journal of pharmaceutical sciences, 79. pp. 27-35.

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Official URL: http://edoc.unibas.ch/40009/

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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 between logDbrain (pH7.4) and the volume of distribution in brain of non-specifically bound tracer in PET was achieved, pertaining to compounds classified as non-substrates of P-glycoprotein (R(2)≥0.88). The ability of LIMBA for the prediction of NSB was further supported by the strong correlation between logDbrain (pH7.4) and NSB in brain autoradiography (R(2)≥0.76), whereas octanol/water distribution coefficients, logDoct (pH7.4) were less predictive. In conclusion, LIMBA provides a fast and reliable tool for identifying compounds with unfavorably high NSB in brain tissue. The data may be used in conjunction with other parameters like target affinity, density and membrane permeability for the selection of most promising compounds to be further investigated in vivo as potential novel PET tracers.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biophysical Chemistry (Seelig A)
UniBasel Contributors:Seelig-Löffler, Anna
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:30 Jun 2016 11:00
Deposited On:30 May 2016 09:17

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