New-generation radiotracers for nAChR and NET

https://doi.org/10.1016/j.nucmedbio.2005.04.017Get rights and content

Abstract

Advances in radiotracer chemistry and instrumentation have merged to make positron emission tomography (PET) a powerful tool in the biomedical sciences. Positron emission tomography has found increased application in the study of drugs affecting the brain and whole body, including the measurement of drug pharmacokinetics (using a positron-emitter-labeled drug) and drug pharmacodynamics (using a labeled tracer). Thus, radiotracers are major scientific tools enabling investigations of molecular phenomena, which are at the heart of understanding human disease and developing effective treatments; however, there is evidently a bottleneck in translating basic research to clinical practice. In the meantime, the poor ability to predict the in vivo behavior of chemical compounds based on their log P's and affinities emphasizes the need for more knowledge in this area. In this article, we focus on the development and translation of radiotracers for PET studies of the nicotinic acetylcholine receptor (nAChR) and the norepinephrine transporter (NET), two molecular systems that urgently need such an important tool to better understand their functional significance in the living human brain.

Introduction

Positron emission tomography (PET) uses radiotracers labeled with short-lived positron emitting isotopes, such as carbon-11 (half-life is 20 min) and F-18 (half-life is 110 min), to track biochemical transformations, changes brought about by disease, as well as the movement of drugs in the living human and animal body. Modern PET research is enriched and strengthened from the integration of many disciplines; however, it is advances in radiotracer chemistry that have played the pivotal role in driving the field in new directions in studies of human physiology. At the heart of this development is synthetic chemistry directed to the rapid incorporation of simple short-lived precursor molecules into organic compounds that can be used to map specific biochemical processes and the movement of drugs in living systems. In this presentation, we will first focus on the development of nAChR radiotracers. We will present how we characterize radiotracers in animals, how we apply tracers to study neuroscience and how we translate a promising radioligand from preclinical investigation in primates to clinical research in humans. We will also touch upon the safety assessment of novel, high-specificity, low-mass radiotracers for use in humans. We will also present some of our recent progress in the development of NET radiotracers, including a discussion of the relationship between the behavior of chemical compounds in vivo and their in vitro properties such as log P and affinities. We will conclude with a perspective on the current scientific and infrastructure needs to facilitate the design and development of new radiotracers and their translation into practice of health care.

Section snippets

Research design and methods

Our overall plan is to develop novel radioligands for imaging various central nervous system (CNS) molecular targets in vivo with PET and to apply these radioligands to examine their roles in the living systems. This involves the development and translation of a lead tracer from the preclinical stage in nonhuman primates through its full characterization in human subjects, including healthy controls and subjects with various CNS disorders.

Examples for development of a new generation of radiotracers for neurotransmitter systems

The development of radiotracers for imaging neurotransmitter systems (including their receptors, their plasma membrane and vesicular transporters, the enzymes which synthesize and degrade them and the processes involved in signal transduction) has dominated radiotracer research. The reasons for this are obvious when one considers that mental processes are driven by the complex interplay of neurotransmitter systems and that their disruption underlies many diseases of the CNS [8]. In the

Outlook

Despite the increasing reliance of the biomedical sciences on imaging, the development of new radiotracers remains a slow process. Even the familiar radiopharmaceuticals that are the backbone of imaging sciences are the product of enormous effort and even serendipity. Yet the value of radiopharmaceuticals in almost every area of clinical research is of such enormous societal importance that it justifies a more focused effort in identifying the impediments and in setting scientific and medical

Long-term needs

The human body presents a complex set of barriers, including the BBB, plasma protein binding, sequestration in cells, nonspecific tissue binding, metabolism, etc., which compete with radiotracer delivery to the target organ. Despite decades of experience, our ability to predict which chemical compounds would have suitable bioavailability, specificity and kinetics required to image and quantify specific molecular targets in the brain and other organs remains limited. As a result, there are a

Acknowledgment

Much of this work was carried out at Brookhaven National Laboratory under contract DE-AC02-98CH10886, with the US Department of Energy and supported by its Office of Biological and Environmental Research and also by the National Institutes of Health (National Institute for Biomedical Imaging and Bioengineering EB002630 and National Institute on Drug Abuse DA-06278) and Office of National Drug Control Policy. We are also thankful to J. Logan, K.-S. Lin, D. Pareto, A. Biegon, H. Benveniste, G.-J.

References (90)

  • U. Scheffel et al.

    6-[18F]Fluoro-A-85380: an in vivo tracer for the nicotinic acetylcholine receptor

    Nucl Med Biol

    (2000)
  • Y.-S. Ding et al.

    Synthesis of 6-[18F]fluoro-3-(S)-azetidinylmethoxy) pyridine for PET studies of nicotine acetylcholine receptors

    Nucl Med Biol

    (2000)
  • A. Carlsson

    The impact of catecholamine research on medical science and practice

  • S.M. Tejani-Butt et al.

    Norepinephrine transporter sites are decreased in the locus coeruleus in Alzheimer's disease

    Brain Res

    (1993)
  • N.R. Zahniser et al.

    Chronic and acute regulation of Na(+)/Cl(−)-dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems

    Pharmacol Ther

    (2001)
  • A. Biegon et al.

    Quantitative autoradiography of 3H-desmethylimipramine binding sites in rat brain

    Eur J Pharmacol

    (1982)
  • M. Van Dort et al.

    Synthesis of 11C-labeled desipramine and its metabolite 2-hydroxydesipramine: potential radiotracers for PET studies of the norepinephrine transporter

    Nucl Med Biol

    (1997)
  • M.S. Haka et al.

    Synthesis and regional mouse brain distribution of [11C]nisoxetine, a norepinephrine uptake inhibitor

    Nucl Med Biol

    (1989)
  • J. McConathy et al.

    Synthesis and biological evaluation of [11C]talopram and [11C]talsupram: candidate PET ligands for the norepinephrine transporter

    Nucl Med Biol

    (2004)
  • M. Tatsumi et al.

    Pharmacological profile of antidepressants and related compounds at human monoamine transporters

    Eur J Pharmacol

    (1997)
  • D.R. Gehlert et al.

    (R)-Thionisoxetine, a potent and selective inhibitor of central and peripheral norepinephrine uptake

    Life Sci

    (1995)
  • A.A. Wilson et al.

    Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter

    Nucl Med Biol

    (2003)
  • M. Schou et al.

    Specific in vivo binding to the norepinephrine transporter demonstrated with the PET radioligand, (S,S)-[11C]MeNER

    Nucl Med Biol

    (2003)
  • K.-S. Lin et al.

    Synthesis, enantiomeric resolution, F-18 labeling and biodistribution of reboxetine analogs: promising radioligands for imaging the norepinephrine transporter with PET

    Nucl Med Biol

    (2005)
  • M.P. Kung et al.

    Selective binding of 2-[125I]iodo-nisoxetine to norepinephrine transporters in the brain

    Nucl Med Biol

    (2004)
  • Y. Kiyono et al.

    Evaluation of radioiodinated (R)-N-methyl-3-(2-iodophenoxy)-3-phenylpropanamine as a ligand for brain norepinephrine transporter imaging

    Nucl Med Biol

    (2004)
  • Y. Charnay et al.

    [3H]Nisoxetine binding sites in the cat brain: an autoradiographic study

    Neuroscience

    (1995)
  • Z. Yavin et al.

    The in vivo binding of 3H-desipramine and 3H-chlorpromazine to areas in the rat brain

    Eur J Pharmacol

    (1978)
  • D.D. Dishino et al.

    Relationship between lipophilicity and brain extraction of C-11-labeled radiopharmaceuticals

    J Nucl Med

    (1983)
  • Y. Huang et al.

    Comparative evaluation in nonhuman primates of five PET radiotracers for imaging the serotonin transporters: [11C]McN 5652, [11C]ADAM, [11C]DASB, [11C]DAPA and [11C]AFM

    J Cereb Blood Flow Metab

    (2002)
  • C.A. Mathis et al.

    Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents

    J Med Chem

    (2003)
  • A. Deutsch et al.

    Neurochemical systems in the central nervous system

  • M. Gopalakrishnan et al.

    Nicotine: therapeutic prospects?

    Pharm News

    (1998)
  • E.F. Domino

    Tobacco smoking and nicotine neuropsychopharmacology: some future research directions

    Neuropsychopharmacology

    (1998)
  • S.P. Arneric et al.

    Neuronal nicotinic acetylcholine receptors — novel targets for central nervous system therapeutics

  • M.R. Picciotto et al.

    Acetylcholine receptors containing the beta2 subunit are involved in the reinforcing properties of nicotine

    Nature

    (1998)
  • D.C. Perry et al.

    Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies

    J Pharmacol Exp Ther

    (1999)
  • R.F. Muzik et al.

    PET quantification of specific binding of carbon-11-nicotine in human brain

    J Nucl Med

    (1998)
  • W. Sihver et al.

    In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)-(−)[11C] nicotine in rhesus monkeys

    Nucl Med Biol

    (1999)
  • T.F. Spande et al.

    Epibatidine: a novel (chloropyridyl) azabicycloheptane with potent analgesic activity from the Equadoran poison frog

    J Am Chem Soc

    (1992)
  • C. Qian et al.

    Epibatidine is a nicotinic analgesic

    Eur J Pharmacol

    (1993)
  • Y.-S. Ding et al.

    Mapping nicotinic acetylcholine receptors with PET

    Synapse

    (1996)
  • A. Horti et al.

    Synthesis of a radiotracer for studying nicotinic acetylcholine receptors: (±)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane

    J Label Cmpd Radiopharm

    (1996)
  • Y.-S. Ding et al.

    Occupancy of brain nicotinic acetylcholine receptors by nicotine doses equivalent to those obtained when smoking a cigarette

    Synapse

    (2000)
  • Y.-S. Ding et al.

    Dopamine receptor-mediated regulation of striatal cholinergic activity: PET studies with [18F]norchlorofluoroepibatidine

    J Neurochem

    (2000)
  • Cited by (0)

    View full text