LogP, a yesterday's value?

Abstract

IntroductionThere 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. MethodLipophilicity 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. ResultsThe 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. ConclusionThe logP determination for prediction of BBB penetration is obsolete.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.