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Application of Cross-Species PET Imaging to Assess Neurotransmitter Release in Brain

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Application of Cross-Species PET Imaging to Assess Neurotransmitter Release in Brain Psychopharmacology (2015) 232:4129–4157 DOI 10.1007/s00213-015-3938-6 REVIEW Application of cross-species PET imaging to assess neurotransmitter release in brain Sjoerd J. Finnema1 & Mika Scheinin2,3 & Mohammed Shahid4 & Jussi Lehto2 & Edilio Borroni5 & Benny Bang-Andersen6 & Jukka Sallinen4 & Erik Wong 7 & Lars Farde1,8 & Christer Halldin1 & Sarah Grimwood9,10 Received: 21 January 2015 /Accepted: 9 April 2015 /Published online: 30 April 2015 # Springer-Verlag Berlin Heidelberg 2015 Abstract neurochemical imaging (PET) methods for drug discovery^, Rationale This review attempts to summarize the current sta- commenced with a focus on developing methods enabling tus in relation to the use of positron emission tomography assessment of changes in extracellular concentrations of sero- (PET) imaging in the assessment of synaptic concentrations tonin and noradrenaline in the brain. of endogenous mediators in the living brain. Results Sharing the workload across institutions, we utilized Objectives Although PET radioligands are now available for in vitro techniques with cells and tissues, in vivo receptor more than 40 CNS targets, at the initiation of the Innovative binding and microdialysis techniques in rodents, and in vivo Medicines Initiative (IMI) BNovel Methods leading to New PET imaging in non-human primates and humans. Here, Medications in Depression and Schizophrenia^ we discuss these efforts and review other recently pub- (NEWMEDS) in 2009, PET radioligands sensitive to an en- lished reports on the use of radioligands to assess changes dogenous neurotransmitter were only validated for dopamine. in endogenous levels of dopamine, serotonin, noradrena- NEWMEDS work-package 5, BCross-species and line, 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- * Sarah Grimwood human primates and human subjects, as well as current chal- [email protected] lenges and future directions. Conclusions PET imaging directed at investigating changes in endogenous neurochemicals, including the work done in 1 Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institutet, Stockholm, Sweden NEWMEDS, have highlighted an opportunity to further ex- tend the capability and application of this technology in drug 2 Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland development. 3 Unit of Clinical Pharmacology, Turku University Hospital, . Turku, Finland Keywords PET imaging Pharmacological challenge 4 Dopamine . Noradrenaline . Serotonin . GABA . Glutamate . Research and Development, Orion Corporation, Orion Pharma, . Turku, Finland Acetylcholine Neurotransmitter Non-human primate 5 Neuroscience Department, Hoffman-La Roche, Basel, Switzerland 6 Neuroscience Drug Discovery, Lundbeck, Copenhagen, Denmark Introduction 7 Neuroscience Innovative Medicine Unit, AstraZeneca, Wilmington, DE, USA Brain imaging with positron emission tomography (PET) is 8 Translational Science Center at Karolinska Institutet, AstraZeneca, now widely used in both academic and industry-driven re- Stockholm, Sweden search for a range of applications in neuroscience research 9 Neuroscience Research Unit, Pfizer Inc, Cambridge, MA, USA and drug discovery. PET radioligands are available for many 10 610 Main Street, Cambridge, MA 02139, USA G-protein-coupled receptors (GPCRs) and neurotransmitter 4130 Psychopharmacology (2015) 232:4129–4157 transporters, as well as some enzymes and ion channels, and in the brain. Here, we discuss these efforts and also review have been used to provide information about the concentra- other recently published reports on the use of radioligands to tion, distribution, and occupancy of specific drug targets in the assess changes in endogenous levels of dopamine, serotonin, central nervous system (CNS) (for reviews see Grimwood and noradrenaline, γ-aminobutyric acid (GABA), glutamate, Hartig 2009; Halldin et al. 2001; Jones et al. 2012; Lee and acetylcholine (ACh), and opioid peptides, also including Farde 2006; Zimmer and Luxen 2012). Molecular imaging detailed summary tables of the PET studies referred to with PET provides high sensitivity when compared to other (Tables 1, 2, 3,and4). Focus has been placed on methods such as single photon emission computed tomog- assessing the availability of appropriate tools (PET raphy (SPECT), and with the recent development of a new radioligand, pharmacological challenge agent) and studies generation of PET systems, also fairly high spatial resolu- in non-human primates and human subjects, as well as tion. The current model of the high-resolution research current challenges and future directions. tomograph (ECAT HRRT; Siemens CTI, Knoxville, TN, USA) allows for spatial image resolution of 1.5 mm when employing point spread function reconstruction and allows Current state of the art: imaging neurotransmitter for reliable imaging of small brain structures (Varrone et al. changes using PET 2009). Moreover, the development of PET systems dedicat- ed to the imaging of rodents has provided opportunities for Dopamine both forward- and back-translation across species and in- creased confidence in the validity of animal models (Nagy The dopamine system has historically been one of the most et al. 2013). extensively studied neurotransmitter systems of the brain. The PET imaging can be employed in the drug development results of these investigations have been fruitful in terms of process in several different ways. First, radiolabeling and ad- basic science and therapeutic applications. Studies on the do- ministration of a microgram dose of the radiolabeled drug can pamine system have over time seen considerable advance- confirm brain exposure using PET (Bergstrom et al. 2003). ments of new technologies and methodological developments. Second, target engagement can be confirmed in a receptor Dopamine was also the first neurotransmitter for which chang- occupancy study in which radioligand and drug interact at es in extracellular concentrations could be evaluated in the the same target. Target engagement has now been demonstrat- living human brain using PET and SPECT (Farde et al. ed for many different drug mechanisms and has provided sig- 1992;Laruelleetal.1995; Volkow et al. 1994). nificant progress towards establishing a better understanding The effects of dopamine are mediated through five receptor of relationships between drug exposure levels and drug target subtypes, divided into two families, the D1-like receptors occupancy, informing dose selection for studies aiming to (D1 and D5)andtheD2-like receptors (D2,D3,andD4) demonstrate therapeutic efficacy in patients (for review see (for review see Vallone et al. 2000). Several dopamine D2- Grimwood and Hartig 2009). One potential confounding fac- like receptor radioligands have now been tested for sensi- tor of target occupancy determinations is that endogenous tivity to endogenous dopamine in experiments conducted ligands may compete directly with radioligand binding. using 3H-labeled radioligands for in vitro or in vivo binding However, this potential interaction raises the opportunity for measurements in rodents, and 11C- or 18F-labeled radioligands a third PET application, to investigate drug-induced changes for in vivo PET measurements in animals or humans. In these in neurotransmitter release, providing insight on receptor studies, extracellular dopamine concentrations in the brain function beyond occupancy as well as modes of drug action. have typically been elevated using amphetamine or methyl- Although PET radioligands are now available for more phenidate, or reduced using reserpine and/or alpha-methyl- than 40 CNS targets, at the initiation of the Innovative para-tyrosine (AMPT), respectively. Medicines Initiative (IMI) BNovel Methods leading to New Initially, the butyrophenone derivatives [3H]spiperone Medications in Depression and Schizophrenia^ (Leysen et al. 1978)and[3H]- and [11C]N-methyl-spiperone (NEWMEDS) in 2009, PET radioligands sensitive to an en- ([3H]/[11C]NMSP) (Lyon et al. 1986; Wagner et al. 1983) dogenous neurotransmitter were limited to dopamine. Spurred were found not to display changes in binding consistent with by the success of developing novel radioligands optimized competition by endogenous dopamine, possibly because these towards assessment of neurotransmitter release, such as the radioligands also bind to intracellular or internalized receptors 11 dopamine D2 receptor agonists [ C]NPA (Narendran et al. (Chugani et al. 1988; for review see Laruelle 2000). The 2004) and [11C]MNPA (Seneca et al. 2006), NEWMEDS substituted benzamide derivatives [11C]raclopride (Ehrin work-package 5, BCross-species and neurochemical imaging et al. 1985)and[123I]IBZM (Kung et al. 1988) have, however, (PET) methods for drug discovery^, commenced with a focus in a large number of animal and human studies, consistently on developing methods enabling assessment of changes in been shown to display changes in binding which are consistent extracellular concentrations of serotonin and noradrenaline with dopamine competition (for review see Laruelle 2000). In Psychopharmacology (2015) 232:4129 a Table 1 PET studies examining the susceptibility of extrastriatal dopamine D2 receptor radioligands for manipulation by dopamine Receptor Radioligand Challenge Species Protocol Outcome Effect on outcome parameter Reference
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