Chrysoula Vraka1, Lukas Nics1, Karl-Heinz Wagner2, Marcus Hacker3, Wolfgang Wadsak4, Markus Mitterhauser5. 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.
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.
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.
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Authors: T Balber; J Singer; N Berroterán-Infante; M Dumanic; L Fetty; J Fazekas-Singer; C Vraka; L Nics; M Bergmann; K Pallitsch; H Spreitzer; W Wadsak; M Hacker; E Jensen-Jarolim; H Viernstein; M Mitterhauser Journal: Contrast Media Mol Imaging Date: 2018-02-13 Impact factor: 3.161
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