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Psychopharmacology (Berl). 2015 Nov;232(21-22):4129-57. doi: 10.1007/s00213-015-3938-6. Epub 2015 Apr 30.

Application of cross-species PET imaging to assess neurotransmitter release in brain.

Author information

1
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
2
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.
3
Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
4
Research and Development, Orion Corporation, Orion Pharma, Turku, Finland.
5
Neuroscience Department, Hoffman-La Roche, Basel, Switzerland.
6
Neuroscience Drug Discovery, Lundbeck, Copenhagen, Denmark.
7
Neuroscience Innovative Medicine Unit, AstraZeneca, Wilmington, DE, USA.
8
Translational Science Center at Karolinska Institutet, AstraZeneca, Stockholm, Sweden.
9
Neuroscience Research Unit, Pfizer Inc, Cambridge, MA, USA. sarah.grimwood@pfizer.com.
10
, 610 Main Street, Cambridge, MA, 02139, USA. sarah.grimwood@pfizer.com.

Abstract

RATIONALE:

This review attempts to summarize the current status in relation to the use of positron emission tomography (PET) imaging in the assessment of synaptic concentrations of endogenous mediators in the living brain.

OBJECTIVES:

Although PET radioligands are now available for more than 40 CNS targets, at the initiation of the Innovative Medicines Initiative (IMI) "Novel Methods leading to New Medications in Depression and Schizophrenia" (NEWMEDS) in 2009, PET radioligands sensitive to an endogenous neurotransmitter were only validated for dopamine. NEWMEDS work-package 5, "Cross-species and neurochemical imaging (PET) methods for drug discovery", commenced with a focus on developing methods enabling assessment of changes in extracellular concentrations of serotonin and noradrenaline in the brain.

RESULTS:

Sharing the workload across institutions, we utilized in vitro techniques with cells and tissues, in vivo receptor binding and microdialysis techniques in rodents, and in vivo PET imaging in non-human primates and humans. Here, we discuss these efforts and review other recently published reports on the use of radioligands to assess changes in endogenous levels of dopamine, serotonin, noradrenaline, γ-aminobutyric acid, glutamate, acetylcholine, and opioid peptides. The emphasis is on assessment of the availability of appropriate translational tools (PET radioligands, pharmacological challenge agents) and on studies in non-human primates and human subjects, as well as current challenges and future directions.

CONCLUSIONS:

PET imaging directed at investigating changes in endogenous neurochemicals, including the work done in NEWMEDS, have highlighted an opportunity to further extend the capability and application of this technology in drug development.

KEYWORDS:

Acetylcholine; Dopamine; GABA; Glutamate; Neurotransmitter; Non-human primate; Noradrenaline; PET imaging; Pharmacological challenge; Serotonin

PMID:
25921033
PMCID:
PMC4600473
DOI:
10.1007/s00213-015-3938-6
[Indexed for MEDLINE]
Free PMC Article

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