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Introduction: Due to the high candidate exclusion rate during a drug development process, an early prediction of the pharmacokinetic behavior would be needed. Accordingly, high performance bioaffinity chromatography (HPBAC) approaches are growing in popularity, however, there is a lack of knowledge and no consensus about the relation between HPBAC measurements, in vivo distribution and blood brain barrier (BBB) penetration behavior. With respect to radiotracers, there is almost no reference data available for plasma protein binding (PPB), permeability (Pm) and the membrane coefficient (K IAM ). Thus, this study was aimed at exploring the relevance of measuring PPB, Pm and K IAM for the prediction of BBB penetration., Methods: Measurements of %PPB, Pm and K IAM were performed using HPBAC. In total, 113 compounds were tested, 43 with brain uptake, 30 not showing brain uptake and 40 with known interactions with efflux transporters. Additionally, ClogP and HPLC logP ow pH7.4 data were collected., Results: %PPB, K IAM , Pm and ClogP values were in the same range for each of the three groups. A significant difference was observed for the HPLC logP ow pH7.4 between CNS penetrating drug group (CNS pos ) and the non-penetrating drug group (CNS neg ), as well as for the CNS neg towards the drug group interacting with efflux transporters (DRUG efflux ). However, as the other experimental data, also the HPLC logP ow pH7.4 showed a broad overlapping of the single values between the groupings., Conclusion: Experimental reference values (logP, Pm, K IAM & PPB) of commonly used PET tracers and drugs showing different BBB penetration behavior are provided. The influence of the logP on brain uptake depends strongly on the selected method. However, using a single parameter (experimental or calculated) to predict BBB penetration or for the classification of drug groups is inexpedient., (Copyright © 2017. Published by Elsevier Inc.)

Introduction: Due to its involvement in a variety of pathologies (obesity, diabetes, gut inflammation and depression), the melanin concentrating hormone receptor 1 (MCHR1) is a new target for the treatment of these lifestyle diseases. We previously presented the radiosynthesis of [(11)C]SNAP-7941, the first potential PET tracer for the MCHR1., Methods: We herein present its in vitro and in vivo evaluation, including binding affinity, plasma stability, stability against liver mircrosomes and carboxylesterase, lipohilicity, biodistribution, in vivo metabolism and small-animal PET., Results: [(11)C]SNAP-7941 evinced high stability against liver microsomes, carboxylesterase and in human plasma. The first small-animal PET experiments revealed a 5 fold increased brain uptake after Pgp/BCRP inhibition. Therefore, it can be assumed that [(11)C]SNAP-7941 is a Pgp/BCRP substrate. No metabolites were found in brain., Conclusion: On the basis of these experiments with healthy rats, the suitability of [(11)C]SNAP-7941 for the visualisation of central and peripheral MCHR1 remains speculative., (Copyright © 2013 Elsevier Inc. All rights reserved.)