pubmed.ncbi.nlm.nih.gov

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

Review

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

Sjoerd J Finnema et al. Psychopharmacology (Berl). 2015 Nov.

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.

PubMed Disclaimer

Figures

Fig. 1
Fig. 1

Translational techniques for measuring changes in endogenous neurotransmitter concentrations with radioligands. A series of experiments is illustrated for validation of measurement of changes in extracellular noradrenaline concentrations using the α2C-AR antagonist [11C]ORM-13070. From left to right: autoradiography of a coronal section of a human brain analyzed by incubation with [3H]ORM-13070 (unpublished results, Karolinska Institutet) and of a rat brain obtained after in vivo [11C]ORM-13070 binding (Arponen et al. 2014). Microdialysis studies demonstrated amphetamine-induced noradrenaline release in rat striatum (Finnema et al. 2014b). PET summation images after injection of [11C]ORM-13070 in a cynomolgus monkey or a human subject (Finnema et al. ; Lehto et al. 2015a)

Fig. 2
Fig. 2

PET radioligands used in NEWMEDS work-package 5. PET summation images of 5-HT1B receptor radioligand [11C]AZ10419369, α2C-AR radioligand [11C]ORM-13070, PDE10A radioligand [11C]Lu AE92686, and GABAA receptor radioligand [11C]RO6899880 in monkey brain

Similar articles

Cited by

References

    1. Aalto S, Ihalainen J, Hirvonen J, Kajander J, Scheinin H, Tanila H, Nagren K, Vilkman H, Gustafsson LL, Syvalahti E, Hietala J. Cortical glutamate-dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology (Berl) 2005;182:375–383. doi: 10.1007/s00213-005-0092-6. - DOI - PubMed
    1. Aalto S, Hirvonen J, Kaasinen V, Hagelberg N, Kajander J, Nagren K, Seppala T, Rinne JO, Scheinin H, Hietala J. The effects of d-amphetamine on extrastriatal dopamine D2/D3 receptors: a randomized, double-blind, placebo-controlled PET study with [11C]FLB 457 in healthy subjects. Eur J Nucl Med Mol Imaging. 2009;36:475–483. doi: 10.1007/s00259-008-0969-9. - DOI - PubMed
    1. Abi-Dargham A, Simpson N, Kegeles L, Parsey R, Hwang DR, Anjilvel S, Zea-Ponce Y, Lombardo I, Van Heertum R, Mann JJ, Foged C, Halldin C, Laruelle M. PET studies of binding competition between endogenous dopamine and the D1 radiotracer [11C]NNC 756. Synapse. 1999;32:93–109. doi: 10.1002/(SICI)1098-2396(199905)32:2<93::AID-SYN3>3.0.CO;2-C. - DOI - PubMed
    1. Airaksinen AJ, Finnema SJ, Balle T, Varnäs K, Bang-Andersen B, Gulyas B, Farde L, Halldin C. Radiosynthesis and evaluation of new alpha1-adrenoceptor antagonists as PET radioligands for brain imaging. Nucl Med Biol. 2013;40:747–754. doi: 10.1016/j.nucmedbio.2013.05.007. - DOI - PubMed
    1. Alpert NM, Badgaiyan RD, Livni E, Fischman AJ. A novel method for noninvasive detection of neuromodulatory changes in specific neurotransmitter systems. Neuroimage. 2003;19:1049–1060. doi: 10.1016/S1053-8119(03)00186-1. - DOI - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources