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


OBJECTIVE
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.
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
Sjoerd J
SJ
Finnema
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.|Unit of Clinical Pharmacology, Turku University Hospital, Turku, Finland.
Mika
M
Scheinin
Research and Development, Orion Corporation, Orion Pharma, Turku, Finland.
Mohammed
M
Shahid
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.
Jussi
J
Lehto
Neuroscience Department, Hoffman-La Roche, Basel, Switzerland.
Edilio
E
Borroni
Neuroscience Drug Discovery, Lundbeck, Copenhagen, Denmark.
Benny
B
Bang-Andersen
Research and Development, Orion Corporation, Orion Pharma, Turku, Finland.
Jukka
J
Sallinen
Neuroscience Innovative Medicine Unit, AstraZeneca, Wilmington, DE, USA.
Erik
E
Wong
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.|Translational Science Center at Karolinska Institutet, AstraZeneca, Stockholm, Sweden.
Lars
L
Farde
Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden.
Christer
C
Halldin
Neuroscience Research Unit, Pfizer Inc, Cambridge, MA, USA. sarah.grimwood@pfizer.com.|, 610 Main Street, Cambridge, MA, 02139, USA. sarah.grimwood@pfizer.com.
Sarah
S
Grimwood
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D006801:Humans; D018377:Neurotransmitter Agents / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D009435:Synaptic Transmission / Q000502:physiology*
D018377:Neurotransmitter Agents
Acetylcholine; Dopamine; GABA; Glutamate; Neurotransmitter; Non-human primate; Noradrenaline; PET imaging; Pharmacological challenge; Serotonin