LogP, a yesterday's value?

Chrysoula Vraka; Lukas Nics; Karl-Heinz Wagner; Marcus Hacker; Wolfgang Wadsak; Markus Mitterhauser

doi:10.1016/j.nucmedbio.2017.03.003

LogP, a yesterday's value?

Nucl Med Biol. 2017 Jul:50:1-10. doi: 10.1016/j.nucmedbio.2017.03.003. Epub 2017 Mar 21.

Authors

Chrysoula Vraka¹, Lukas Nics¹, Karl-Heinz Wagner², Marcus Hacker³, Wolfgang Wadsak⁴, Markus Mitterhauser⁵

Affiliations

¹ Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department for Nutritional Science, University of Vienna, Vienna, Austria.
² Department for Nutritional Science, University of Vienna, Vienna, Austria.
³ Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
⁴ Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of Inorganic Chemistry, University of Vienna, Vienna, Austria; CBmed, Graz, Austria.
⁵ Department of Biomedical Imaging and Image-guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria; Department of (PTB) Pharmaceutical Technology and Biopharmaceuticals, University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute Applied Diagnostics, Vienna, Austria. Electronic address: markus.mitterhauser@meduniwien.ac.at.

PMID: 28364662
DOI: 10.1016/j.nucmedbio.2017.03.003

Abstract

Introduction: There is an increasing demand for high throughput methods at early stages of preclinical radioligand development, in order to predict pharmacokinetic properties (e.g., biodistribution) and blood brain barrier (BBB) penetration. One of the most important physicochemical properties is the lipophilicity, measured by means of shake-flask (logP) or HPLC methods. Yet, a plethora of experimental methods are described in the literature for the determination of logP values. These varying methods often lead to different results for one identical compound, which complicates any comparison or prediction for subsequent preclinical studies. However, a standardized and internationally applied and accepted database with logP values for a reliable comparison of the lipophilic character of radiotracers is still missing.

Method: Lipophilicity measurements were performed with 121 molecules using a high throughput HPLC method and ClogP values were calculated using ChemBioDraw®. Furthermore, logP measurements for six representative radiotracers were performed with the conventional shake-flask method and the results were statistically compared to the ClogP and HPLC logP results. Different logP thresholds, suggesting optimal BBB penetration according to literature, were selected and put into relation with the acquired HPLC logP and ClogP values of cerebral tracers.

Results: The results of the tested compounds ranged from -2.1 to 5.4 with the applied HPLC method. The acquired database comprises ClogP values of the whole set of compounds ranging from -4.11 to 6.12. LogP data from different methods were not comparable. The correlation of the obtained logP data to thresholds suggesting an optimal brain uptake resulted in a high number of false positive classifications.

Conclusion: The logP determination for prediction of BBB penetration is obsolete. The extensive database, including clinical relevant radiotracers, can be used as comparative set of values for preclinical studies, and serves as a basis for further critical discussions concerning the eligibility of logP.

Keywords: Blood brain barrier; Database; HPLC logP; Lipophilicity; Radioligand &-tracer.

MeSH terms

Chromatography, High Pressure Liquid
Databases, Pharmaceutical
Drug Discovery*
Hydrophobic and Hydrophilic Interactions*
Ligands

Substances

Ligands

Grants and funding

P 26502/FWF_/Austrian Science Fund FWF/Austria