Current Topics in Medicinal Chemistry

ISSN:1568-0266

Current Topics in Medicinal Chemistry
Volume 10, Number 15, 2010

Contents

Recent Advances in the Medicinal Radiochemistry of Radioligands for Cerebral In Vivo Imaging
Guest Editors: Andrew G. Horti and Robert F. Dannals


Editorial Pp. 1476


Current State of Agonist Radioligands for Imaging of Brain Dopamine D₂/D₃ Receptors In Vivo with Positron Emission Tomography Pp. 1477-1498
Sjoerd J. Finnema, Benny Bang-Andersen, Håkan V. Wikström and Christer Halldin
[Abstract] [Purchase Article]


Development of Effective PET and SPECT Imaging Agents for the Serotonin Transporter: Has a Twenty-Year Journey Reached its Destination? Pp. 1499-1526
Yiyun Huang, Ming-Qiang Zheng and John M. Gerdes
[Abstract] [Purchase Article]


Non-Invasive Imaging of the Type 2 Cannabinoid Receptor, Focus on Positron Emission Tomography Pp. 1527-1543
Nele Evens and Guy M. Bormans
[Abstract] [Purchase Article]


Recent Development of Radioligands for Imaging α7 Nicotinic Acetylcholine Receptors in the Brain Pp. 1544-1557
Jun Toyohara, Jin Wu and Kenji Hashimoto
[Abstract] [Purchase Article]


Radioligands for the PET Imaging of Metabotropic Glutamate Receptor Subtype 5 (mGluR5) Pp. 1558-1568
Linjing Mu, P. August Schubiger and Simon M. Ametamey
[Abstract] [Purchase Article]


PET Radioligands for the Vesicular Acetylcholine Transporter (VAChT) Pp. 1569-1583
Nicolas Giboureau, Ian Mat Som, Aurélie Boucher-Arnold, Denis Guilloteau and Michael Kassiou
[Abstract] [Purchase Article]



Abstracts

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Current State of Agonist Radioligands for Imaging of Brain Dopamine D₂/D₃ Receptors In Vivo with Positron Emission Tomography
Sjoerd J. Finnema, Benny Bang-Andersen, Håkan V. Wikström and Christer Halldin

Dopamine (DA) is known to play an important role in numerous brain functions and has been suggested to be involved in several neuropsychiatric and neurological disorders. From early on, positron emission tomography (PET) studies of the DA system have yielded high interest. Currently, several aspects of the functionality of DA neurons can be imaged, including the DA synthesis rate and the expression of DA-related proteins (receptors and transporters). A more recent application of radioligands targeting DA receptors is to study the endogenous neurotransmitter levels in vivo in brain.

In vitro binding studies have suggested that in general DA receptors, as many other G-protein coupled receptors, exist in two affinity states for agonist binding. The high affinity state is thought to represent the functional state of the receptor, and the proportion between high and low affinity states may change with the development of disease. PET imaging with agonist radioligands may provide information on the existence of the high affinity state in vivo. In addition, DA receptor agonist radioligands may be superior tools for measuring changes in endogenous DA levels as antagonist radioligands inherently bind to both the low and the high affinity state.

This review primarily summarizes the current status of agonist PET radioligands targeting the D₂ and D₃ receptor (D₂/D₃ receptor). In addition several PET studies evaluating the utility of the agonist concept are discussed.


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Development of Effective PET and SPECT Imaging Agents for the Serotonin Transporter: Has a Twenty-Year Journey Reached its Destination?
Yiyun Huang, Ming-Qiang Zheng and John M. Gerdes

The serotonin transporter (SERT) has been implicated in a variety of neuropsychiatric disorders including depression, schizophrenia, substance abuse, alcoholism, and Alzheimer’s disease. Radiotracer-based in vivo imaging techniques such as Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) are important tools to investigate the functions of SERT in the living brain under normal conditions and its dysfunction in diseases. In this report we review the development and validation of effective PET and SPECT radiotracers in the last twenty years. First, the requirements for an effective imaging tracer, and factors influencing a tracer’s in vivo imaging performance are discussed. PET and SPECT radiotracers for SERT are then categorized and reviewed according to their chemical scaffolds: 1) SSRIs and related compounds; 2) tropane-based ligands; 3) isoquinolines; and 4) substituted diarylsulfides. Critical evaluation and comments are provided for promising radiotracers, if any, emerging from each chemical scaffold. Based on experimental data gathered from radiotracer development for SERT, an examination of the relationship between an imaging tracer’s in vitro physicochemical and pharmacological properties and its in vivo performance parameters is provided. Finally, tracers available for imaging applications in humans are assessed and compared in terms of tissue binding kinetics, non-specific binding, and specific binding signals in vivo. From these assessments, we conclude that, after twenty years of development efforts, a number of effective PET and SPECT radiotracers have now been validated and are available for imaging SERT in humans. The applications of these efficacious SERT imaging agents will further advance our understanding of this important transporter in psychiatric and neurodegenerative disorders.


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Non-Invasive Imaging of the Type 2 Cannabinoid Receptor, Focus on Positron Emission Tomography
Nele Evens and Guy M. Bormans

The type 2 cannabinoid receptor (CB₂R) is a relatively new target for drug development, as the receptor was only discovered in 1993. The CB₂R is mainly expressed in tissues and organs related to the immune system. However, in pathological conditions, mostly inflammatory, a strong upregulation has been observed. Because of its expression in activated microglia, the type 2 cannabinoid receptor might play an important role in pathologies with a neuroinflammatory component. Positron emission tomography provides a sensitive non-invasive imaging technique to study and quantify receptor expression. In this review, the importance of CB₂R imaging, the current status and the future possibilities for the development of CB₂R PET radioligands are discussed.


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Recent Development of Radioligands for Imaging α7 Nicotinic Acetylcholine Receptors in the Brain
Jun Toyohara, Jin Wu and Kenji Hashimoto

The α7 nicotinic acetylcholine receptors (nAChRs), ligand-gated Ca²⁺ channels composed of homopentamers of α7 subunits, represent the most abundant with α4β2 nAChRs in the brain. Several lines of evidence suggest that α7 nAChRs play a role in the physiology of neuropsychiatric diseases such as schizophrenia, Alzheimer’s disease, anxiety, depression, and drug addiction; hence, α7 nAChRs seem to be attractive therapeutic targets for these diseases. Several researchers have attempted to develop radioligands that can be used to selectively and quantitatively examine the distribution of α7 nAChRs in the human brain with positron emission tomography (PET) or single photon emission tomography (SPECT). Although efforts are underway, very low density of α7 nAChR and scarcity of very high affinity ligands hamper the development of α7 subtype-selective radioligands for in vivo imaging. In this article, we review the recent topics on the development of PET/SPECT ligands for in vivo imaging of α7 nAChRs in the brain.


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Radioligands for the PET Imaging of Metabotropic Glutamate Receptor Subtype 5 (mGluR5)
Linjing Mu, P. August Schubiger and Simon M. Ametamey

Metabotropic glutamate receptors (mGluRs) are G-protein coupled receptors (GPCR), which activate intracellular secondary messenger systems when bound by the physiological ligand glutamate. Modulation of mGluR5s has potential for the treatment of variety of psychiatric and neurological diseases such as depression, anxiety, schizophrenia and Parkinson's disease.

Positron emission tomography (PET) might offer the possibility to visualize the mGluR5 and present an interesting tool for studying this receptor-subtype under physiologic and pathologic conditions. In this review paper, emphasis is given to the radiosynthesis, in vitro and in vivo characterization of recently published mGluR5 PET tracers.

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PET Radioligands for the Vesicular Acetylcholine Transporter (VAChT)
Nicolas Giboureau, Ian Mat Som, Aurélie Boucher-Arnold, Denis Guilloteau and Michael Kassiou

The vesicular acetylcholine transporter (VAChT) is a glycoprotein responsible for the accumulation of acetylcholine into pre-synaptic vesicules of cholinergic neurons. Cholinergic innervation has been shown to be decreased at the earlier stages of Alzheimer’s disease (AD). Thus, the expression of VAChT has been correlated with the severity of the dementia and has been considered as a significant diagnostic target for AD. To this end numerous radioligands based on the vesamicol scaffold have been developed for imaging the VAChT using positron emission tomography (PET). Among the various radioligands only a small number have been evaluated in vivo in non-human primate and human. Despite promising in vitro, ex vivo and first in vivo studies, most of them are unsuitable for clinical use in humans due to poor selectivity over σ receptors, low extraction from the blood, slow brain kinetics or fast metabolism. To date (-)-[¹¹C]OMV (1), (-)-[¹¹C]MABV (2), (-)-[¹⁸F]-FEOBV (6), (-)-trans-2-hydroxy-3-(4-(4-[¹⁸F]fluorobenzoyl)piperidine) tetralin (8) and [¹⁸F]FBMV (12) are promising radioligands for the VAChT, though further validation is required to confirm their clinical usefulness.