Tachykinins and their receptors in PET
Tachykinins (TKs) are evolutionary ancient neuropeptides that include vertebrate substance P (SP), mammalian neurokinin A (NKA), neuropeptide K (NPK), neuropeptide γ (NPγ), and neurokinin B (NKB) (Steinhoff et al., 2014; Nässel et al., 2019). In mammals, three related genes produce preprotachykinin proteins, from which the tachykinins are spliced. Mammals have three TK receptors, NK1-3R (or TAC1-3R), which belong to the superfamily of G protein-coupled receptors (GPCRs), more specifically to the rhodopsin family (family A GPCRs). TK receptors are desensitized by endocytosis, β-arrestins, and/or phosphorylation, and resensitized by dephosphorylation and by recycling to the plasma membrane. TKs have differing affinity for the tachykinin receptors (Nässel et al., 2019):
- NK1R: SP > NKA > NKB
- NK2R: NKA > NKB > SP
- NK3R: NKB > NKA > SP
TKs work as neuromodulators/cotransmitters in mammalian central and peripheral nervous system and immune system, playing roles in inflammation, sensory processing, memory formation, and respiratory, gastrointestinal, urogenital, and dermal systems. TKs contribute to numerous disease processing, such as chronic inflammation and fibrosis, pain, cancer, functional disorders of the intestine and urinary bladder, and affective and addictive disorders (Steinhoff et al., 2014; Nässel et al., 2019).
NK1 receptors are present in the central and peripheral nervous system, smooth muscle, endothelial cells, and immune cells (Schöppe et al., 2019). Substance P is the preferential endogenous agonist of NK1R, and the SP-NK1R system has been linked to nausea, analgesia, inflammation, itching, and depression, and has led to development of many peptide and non-peptide antagonists and agonists of NK1R (Majkowska-Pilip et al., 2019; Schöppe et al., 2019). NK1R antagonist aprepitant is used for treatment of nausea and itch. NK1Rs are upregulated in inflamed organs. SP and NKA are released from sensory nerves in the skin as response to many exogenous and endogenous stimuli. Over-expression of NK1 receptors has been implicated in cancer progression and poor prognosis, and numerous radioligands have been developed for tumour diagnosis and radiotherapy (Majkowska-Pilip et al., 2019).
Antagonist PET radioligands include [11C]GR205171 (Bergström et al., 2000; Zamuner et al., 2012), [18F]SPA-RQ (Solin et al., 2004; Bergström et al., 2004), [18F]FE-SPA-RQ (Haneda et al., 2007; Okumura et al., 2008), [11C]R116301 (Wolfensberger et al., 2009 and 2011).
The NK1Rs in guinea pigs resembles those in humans, and guinea pigs have been shown to be useful for preclinical studies with NK1R antagonist radioligands (Grönroos et al., 2019).
NK1 receptors are upregulated in inflamed organs.
The NK3Rs and NKB have an important role in hypothalamic-pituitary-gonadal axis in humans. NK3R agonists stimulate dopaminergic neurotransmission, and antagonists inhibit dopamine release.
Antagonist radioligand [18F]Lu AF10628 has been used in vivo in guinea pigs and monkeys, and in vitro with human brain tissue, but results were not very promising because of relatively high uptake of free fluoride in the skull bone (Varnäs et al., 2016).
Holzer P (ed.): Tachykinins. Springer, 2004. doi: 10.1007/978-3-642-18891-6.
Kastin AJ (ed.): Handbook of Biologically Active Peptides, 2nd ed., Academic Press, 2013. eISBN: 9780123850966.
Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW. Tachykinins and their receptors: contribution to physiological control and the mechanisms of disease. Physiol Rev. 2014; 94: 265-301. doi: 10.1152/physrev.00031.2013.
Updated at: 2020-01-02
Created at: 2020-01-01
Written by: Vesa Oikonen