FPTQ

6-[1-(2-[18F]Fluoro-3-pyridyl)-5-methyl-1 H-1,2,3-triazol-4-yl]quinoline

Glutamate is a major excitatory neurotransmitter at neuronal synapses in the central nervous system (CNS) (1, 2). Glutamate produces its excitatory effects by acting on cell-surface ionotropic glutamate or metabotropic glutamate receptors (mGluRs). The mGluRs are GTP-binding protein (G-protein)–coupled receptors that play important roles in regulating the activity of many synapses in the CNS, and many neuronal projection pathways contain mGluRs. There are eight mGluR subtypes, which are further subdivided into groups I, II, and III. The group I receptors include mGluR1 and mGluR5, and they are found predominantly in postsynaptic locations. The mGluR1 is found in moderate to high density in the cerebellum, caudate, putamen, thalamus, cingulate cortex, and hippocampus, with low density in the pons. The mGluR5 is usually found in moderate to high density in the frontal cortex, caudate, putamen, nucleus accumbens, olfactory tubercle, and hippocampus, whereas the density in the cerebellum is low. The mGluR1 and mGluR5 are positively coupled to phospholipase C in the regulation of neuronal excitability (3). Dysfunction of mGluR1 and mGluR5 is implicated in a variety of diseases in the CNS, including anxiety, depression, schizophrenia, Parkinson’s disease, and drug addiction or withdrawal (2, 4).

Positron emission tomography (PET) and single-photon emission tomography of radioligands targeting mGluR1 can visualize and analyze mGluR1 expression in normal physiological and pathological conditions. Several radioligands have been studied for in vivo imaging of mGluR1 in the brain (5). 6-[1-(2-(Fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline (FPTQ) was shown to be a selective mGluR1 with nanomolar affinity (3.6 nM), with little inhibition to mGluR5 (6). Fujinaga et al. (7) prepared and evaluated 6-[1-(2-[18F] fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline ([18F]FPTQ) for use with in vivo PET imaging of mGluR1 distribution in rats. The investigators concluded that [18F]FPTQ is not suitable for PET imaging of GluR1 in the brain because of its rapid dissociation and the presence of radiolabeled metabolite in the brain.

Anti-inflammatory effect of a novel synthetic compound 1-((4-fluorophenyl)thio)isoquinoline in RAW264.7 macrophages and a zebrafish model

The compound, 1-((4-fluorophenyl)thio)isoquinoline (FPTQ), is a synthetic isoquinoline derivative. To test the anti-inflammatory effect of FPTQ, we used neutrophil-specific transgenic zebrafish Tg(mpx::EGFP)ⁱ¹¹⁴ line and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. We also used two different methods, involving tail transection and LPS stimulation in the zebrafish model. Neutrophils translocation in the zebrafish tail-transected model was inhibited by FPTQ. Neutrophil aggregation was also inhibited by FPTQ in the LPS-stimulated zebrafish model. Decreased mRNA expression of the pro-inflammatory cytokine genes, interleukin-1β (il-1β) and interleukin-6 (il-6), was found in zebrafish larvae injected with FPTQ. Additionally, production of nitric oxide was inhibited by FPTQ in RAW264.7 macrophage cells treated with LPS. Moreover, the mRNA expression of Il-1β and Il-6 suppressed by FPTQ treatment in RAW264.7 macrophage cells, and an enzyme immunoassay showed that FPTQ suppressed the secretion of IL-1β and IL-6 in RAW264.7 cells. These results demonstrate that FPTQ reduced inflammatory responses and, therefore, suggest that it may be effective as an anti-inflammatory agent.

Synthesis and evaluation of 6-[1-(2-[(18)F]fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline for positron emission tomography imaging of the metabotropic glutamate receptor type 1 in brain

The purpose of this study was to synthesize 6-[1-(2-[(18)F]fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline ([(18)F]FPTQ, [(18)F]7a) and to evaluate its potential as a positron emission tomography ligand for imaging metabotropic glutamate receptor type 1 (mGluR1) in the rat brain. Compound [(18)F]7a was synthesized by [(18)F]fluorination of 6-[1-(2-bromo-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline (7b) with potassium [(18)F]fluoride. At the end of synthesis, 1280-1830MBq (n=8) of [(18)F]7a was obtained with >98% radiochemical purity and 118-237GBq/μmol specific activity using 3300-4000MBq of [(18)F]F(-). In vitro autoradiography showed that [(18)F]7a had high specific binding with mGluR1 in the rat brain. Biodistribution study using a dissection method and small-animal PET showed that [(18)F]7a had high uptake in the rat brain. The uptake of radioactivity in the cerebellum was reduced by unlabeled 7a and mGluR1-selective ligand JNJ-16259685 (2), indicating that [(18)F]7a had in vivo specific binding with mGluR1. Because of a low amount of radiolabeled metabolite present in the brain, [(18)F]7a may have a limiting potential for the in vivo imaging of mGluR1 by PET.