ArticleDetermination of lipophilicity and its use as a predictor of blood–brain barrier penetration of molecular imaging agents
Section snippets
Compound lipophilicity in therapeutic drug development
The molecular characteristics traditionally considered during drug development include affinity and selectivity for the target site, metabolic profile, lipophilicity, and molecular size and weight (for reviews1., 2., 3., 4., 5.). Many of these attributes are interdependent and important to optimize during both the development of therapeutic drugs and effective site-specific radiotracers. This paper focuses on the importance of lipophilicity and its impact on the effectiveness of positron
How is lipophilicity measured?
The International Union of Pure and Applied Chemistry (IUPAC) definition of lipophilicity states that lipophilicity is the affinity of a molecule or moiety for a lipophilic environment.5., 6. Contributors to lipophilicity include molecular size and weight, and hydrogen bonding capacity [hydrogen donors and acceptors affecting ionization (pKa)]. Lipophilicity is measured in various theoretical and experimental ways and many of these are reviewed in this section. The most common experimental
Drug characteristics required for good tissue absorption
As discussed above, compound lipophilicity is a fundamental physicochemical property that plays a pivotal role in the absorption, distribution, metabolism, and elimination (ADME) of therapeutic drugs. Decades of drug development efforts have revealed specific relationships between key physicochemical attributes and organ uptake that are widely documented throughout the literature. In particular, it has been established that poor tissue absorption occurs when the molecular weight is greater than
Lipophilicity in tracer development: is it truly important?
As noted above, the important contributions of drug lipophilicity to drug brain uptake and overall ADME have been fairly well explored, and several established relationships are documented. However, during classical radiotracer experiments, the amount of mass administered is several hundred-fold lower than doses typically given for therapeutic drugs. Since several of the biological obstacles encountered in the journey of a molecule through the bloodstream and across the BBB involve saturable
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