Cover Feature: A Comparative Study of in?vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in?vivo (ChemMedChem 7/2020) |
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| Authors: | Dr Luca Gobbi Dr Joël Mercier Dr Benny Bang-Andersen Dr Jean-Marie Nicolas Dr John Reilly Björn Wagner Dr David Whitehead Dr Emmanuelle Briard Dr R Paul Maguire Dr Edilio Borroni Dr Yves P Auberson |
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| Affiliation: | 1. Pharma Research and Early Development, Roche Innovation Center Basel F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland;2. UCB Early Solutions, UCB Biopharma sprl, 1420 Braine-l'Alleud, Belgium;3. Molecular Discovery and Innovation, H. Lundbeck A/S, 9 Ottiliavej, 2500 Valby, Denmark;4. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Fabrikstrasse 2, 4056 Basel, Switzerland |
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| Abstract: | Nonspecific binding (NSB) is a key parameter in optimizing PET imaging tracers. We compared the ability to predict NSB of three available methods: LIMBA, rat fu,brain, and CHI(IAM). Even though NSB is often associated with lipophilicity, we observed that logD does not correlate with any of these assays, clearly indicating that lipophilicity, while influencing NSB, is insufficient to predict it. A cross-comparison of the methods showed that all three correlate and are useful predictors of NSB. The three assays, however, rank the molecules slightly differently, illustrating the challenge of comparing molecules within a narrow chemical space. We also noted that CHI(IAM) values more effectively predict VNS, a measure of in vivo NSB in the human brain. CHI(IAM) measurements might be a closer model of the actual physicochemical interaction between PET tracer candidates and cell membranes, and seems to be the method of choice for the optimization of in vivo NSB. |
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| Keywords: | imaging agents radiopharmaceuticals nonspecific binding positron emission tomography fraction unbound |
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