Elsevier

Molecular Imaging & Biology

Volume 5, Issue 6, November–December 2003, Pages 376-389
Molecular Imaging & Biology

Article
Determination of lipophilicity and its use as a predictor of blood–brain barrier penetration of molecular imaging agents

https://doi.org/10.1016/j.mibio.2003.09.014Get rights and content

Abstract

Compound lipophilicity is a fundamental physicochemical property that plays a pivotal role in the absorption, distribution, metabolism, and elimination (ADME) of therapeutic drugs. Lipophilicity is expressed in several different ways, including terms such as Log P, clogP, delta Log P, and Log D. Often a parabolic relationship exists between measured lipophilicity and in vivo brain penetration of drugs, where those moderate in lipophilicity often exhibit highest uptake. Reduced brain extraction of more lipophilic compounds is associated with increased non-specific binding to plasma proteins. More lipophilic compounds can also be more vulnerable to P450 metabolism, leading to faster clearance. Very polar compounds normally exhibit high water solubility, fast clearance through the kidneys, and often contain ionizable functional groups that limit blood–brain barrier (BBB) penetration.

The brain penetration and specific to non-specific binding ratios exhibited in vivo by positron emission tomography (PET) and single photon emission computed tomography (SPECT) radiotracers involves a complex interplay between many critical factors, including lipophilicity, receptor affinity, metabolism, molecular size and shape, ionization potential, and specific binding to BBB efflux pumps or binding sites on albumin or other plasma proteins. This paper explores situations in which lipophilicity is a good predictor of BBB penetration, as well as those where this correlation is poor. The more commonly used methods for measuring lipophilicity are presented, and the various terms often found in the literature outlined. An attempt is made to describe how this information can be used in optimizing the development of PET and SPECT tracers that target the central nervous system (CNS).

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

References (137)

  • F.A. Gobas et al.

    A novel method for measuring membrane-water partition coefficients of hydrophobic organic chemicals: comparison with 1-octanol-water partitioning

    J. Pharm. Sci

    (1988)
  • N. Gulyaeva et al.

    Relative hydrophobicity of organic compounds measured by partitioning in aqueous two-phase systems

    J. Chromatogr. B. Analyt. Technol. Biomed. Sci

    (2000)
  • P. Ruelle

    The n-octanol and n-hexane/water partition coefficient of environmentally relevant chemicals predicted from the mobile order and disorder (MOD) thermodynamics

    Chemosphere

    (2000)
  • A.A. Wilson et al.

    An admonition when measuring the lipophilicity of radiotracers using counting techniques

    Appl. Radiat. Isot

    (2001)
  • J.C. Caron et al.

    Determination of partition coefficients of glucocorticosteroids by high-performance liquid chromatography

    J. Pharm. Sci

    (1984)
  • R. Kaliszan et al.

    Lipophilicity and pKa estimates from gradient high-performance liquid chromatography

    J. Chromatogr. A

    (2002)
  • R. Pignatello et al.

    Lipophilicity evaluation by RP-HPLC of two homologous series of methotrexate derivatives

    Pharma. Acta Helv

    (2000)
  • K. Valko et al.

    Rapid-gradient HPLC method for measuring drug interactions with immobilized artificial membrane: comparison with other lipophilicity measures

    J. Pharm. Sci

    (2000)
  • P.L. Bonate

    Animal models for studying transport across the blood-brain barrier

    J. Neurosci. Meth

    (1995)
  • M.J. Welch et al.

    Biodistribution of N-alkyl and N-fluoroalkyl derivatives of spiroperidol; radiopharmaceuticals for PET studies of dopamine receptors

    International Journal of Radiation Applications and Instrumentation. Part B

    (1986)
  • R.N. Waterhouse et al.

    In vivo evaluation of [18F]1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl) piperidine: a selective sigma-1 receptor radioligand for PET

    Nucl. Med. Biol

    (1997)
  • R.N. Waterhouse et al.

    Evaluation of [(3)H]LY341495 for labeling group II metabotropic glutamate receptors in vivo

    Nucl. Med. Biol

    (2003)
  • R.N. Waterhouse et al.

    In vivo evaluation of [11C]-3-[2-[(3-methoxyphenylamino) carbonyl]ethenyl]-4, 6-dichloroindole-2-carboxylic acid ([11C]3MPICA) as a PET radiotracer for the glycine site of the NMDA ion channel

    Nucl. Med. Biol

    (2002)
  • R.N. Waterhouse et al.

    In vivo evaluation of [123I]8-[4-[2-(5-iodothienyl)]-4-oxobutyl]-3-methyl-1-phenyl-1, 3, 8-tri azaspiro[4.5]decan-4-one as a potential dopamine D2 receptor radioligand for SPECT

    Nucl. Med. Biol

    (1998)
  • J. Mukherjee et al.

    N-(6–18F-fluorohexyl)-N-methylpropargylamine: a fluorine-18-labeled monoamine oxidase B inhibitor for potential use in PET studies

    Nucl. Med. Biol

    (1999)
  • J. Mukherjee et al.

    Development of N-[3-(2′, 4′-dichlorophenoxy)-2–18F-fluoropropyl]-N-methylpropargylamine (18F-fluoroclorgyline) as a potential PET radiotracer for monoamine oxidase-A

    Nucl. Med. Biol

    (1999)
  • O. Langer et al.

    High specific radioactivity (1R, 2S)-4-[(18)F]fluorometaraminol: a PET radiotracer for mapping sympathetic nerves of the heart

    Nucl. Med. Biol

    (2000)
  • T.R. DeGrado et al.

    Synthesis and preliminary evaluation of (18)F-labeled 4-thia palmitate as a PET tracer of myocardial fatty acid oxidation

    Nucl. Med. Biol

    (2000)
  • P. Carnochan et al.

    Radiolabelled 5′-iodo-2′-deoxyuridine: a promising alternative to [18F]-2-fluoro-2-deoxy-D-glucose for PET studies of early response to anticancer treatment

    Nucl. Med. Biol

    (1999)
  • A.A. Wilson et al.

    In vitro and in vivo characterisation of [11C]-DASB: a probe for in vivo measurements of the serotonin transporter by positron emission tomography

    Nucl. Med. Biol

    (2002)
  • F. Sobrio et al.

    Radiosynthesis of [18F]Lu29–024: a potential PET ligand for brain imaging of the serotonergic 5–HT2 receptor

    Bioorg. Med. Chem

    (2000)
  • A. Fredriksson et al.

    In vivo evaluation of the biodistribution of 11C-labeled PD153035 in rats without and with neuroblastoma implants

    Life Sci

    (1999)
  • V.I. Cohen et al.

    In vitro and in vivo m2 muscarinic subtype selectivity of some dibenzodiazepinones and pyridobenzodiazepinones

    Brain Res

    (2000)
  • T. Haradahira et al.

    Synthesis, in vitro and in vivo pharmacology of a C-11 labeled analog of CP-101, 606, (+/−)threo-1-(4-hydroxyphenyl)-2-[4-hydroxy-4-(p-[11C]methoxyphenyl)piperidino]1-propanol, as a PET tracer for NR2B subunit-containing NMDA receptors

    Nucl. Med. Biol

    (2002)
  • S. Samnick et al.

    Preparation of 8-[3-(4-fluorobenzoyl)-propyl]-1-(4-[123I] iodobenzoyl)-1, 3,8-triazaspiro[4, 5] decan-4-one: a novel selective serotonin 5–HT2 receptor agent

    Nucl. Med. Biol

    (1997)
  • A. Avdeef

    Physicochemical profiling (solubility, permeability and charge state)

    Curr. Top. Med. Chem

    (2001)
  • H. van de Waterbeemd et al.

    Lipophilicity in PK design: methyl, ethyl, futile

    J. Comput. Aided Mol. Des

    (2001)
  • H. Tanaka et al.

    Drug-protein binding and blood-brain barrier permeability

    J. Pharmacol. Exp. Ther

    (1999)
  • P. Jolliet Riant et al.

    Drug transfer across the blood-brain barrier and improvement of brain delivery

    Fundam. Clin. Pharmacol

    (1999)
  • P. Jolliet Riant et al.

    Mechanisms of nutrient and drug transfer through the blood-brain barrier and their pharmacological changes

    Encephale

    (1999)
  • J.B. Van Bree et al.

    Drug transport across the blood–brain barrier. I. Anatomical and physiological aspects

    Pharm. Weekbl. Sci

    (1992)
  • R.A. Hawkins et al.

    The complementary membranes forming the blood-brain barrier

    IUBMB Life

    (2002)
  • A.L. Betz

    Epithelial properties of brain capillary endothelium

    Fed. Proc

    (1985)
  • R. Bendayan et al.

    Functional expression and localization of P-glycoprotein at the blood brain barrier

    Microsc. Res. Tech

    (2002)
  • K.M. Doan et al.

    Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs

    J. Pharmacol. Exp. Ther

    (2002)
  • M.S. Malandro et al.

    Molecular biology of mammalian amino acid transporters

    Annu. Rev. Biochem

    (1996)
  • M.S. Kilberg et al.

    Recent advances in mammalian amino acid transport

    Annu. Rev. Nutr

    (1993)
  • F. Jursky et al.

    Structure, function and brain localization of neurotransmitter transporters

    J. Exp. Biol

    (1994)
  • M.A. Hediger et al.

    Introduction: glutamate transport, metabolism, and physiological responses

    Am. J. Physiol

    (1999)
  • H. van de Waterbeemd et al.

    Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors

    J. Drug Target

    (1998)
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