作者: Françoise Hinnen ; Frédéric Dollé ; Héric Valette ; Marcel Delaforge ; Christian Loc'h ; Laurent Besret ; Mylène Karramkam ; Yann Bramoullé ; Sébastien Bourg ; Michel Bottlaender ; Françoise Vaufrey ; Carine Franklin ; Michèle Ottaviani ; Christian Crouzel ; Christine Coulon

Considerable efforts have been engaged in the design, synthesis and pharmacological characterization of radioligands for imaging the serotonin transporter, based on its implication in several neuropsychiatric diseases, such as depression, anxiety and schizophrenia. In the 5-halo-6-nitroquipazine series, the fluoro derivative has been designed for positron emission tomography (PET). The corresponding 5-iodo-, 5-bromo- and 5-chloro N-Boc-protected quipazines as labelling precursors, as well as 5-fluoro-6-nitroquipazine as a reference compound have been synthesized. 5-[(18)F]Fluoro-6-nitroquipazine has been radiolabelled with fluorine-18 (positron-emitting isotope, 109.8 min half-life) by nucleophilic aromatic substitution from the corresponding N-Boc protected 5-bromo- and 5-chloro-precursors using K[(18)F]F-K(222) complex in DMSO by conventional heating (145 degrees C, 2 min) or microwave activation (50 W, 30-45 s), followed by removal of the protective group with TFA. Typically, 15-25 mCi (5.5-9.2 GBq) of 5-[(18)F]fluoro-6-nitroquipazine (1-2 Ci/micromol or 37-72 GBq/micromol) could be obtained in 70-80 min starting from a 550-650 mCi (20.3-24.0 GBq) aliquot of a cyclotron [(18)F]F(-) production batch (2.7-3.8% non decay-corrected yield based on the starting [(18)F]fluoride). Ex vivo studies (biodistribution in rat), as well as PET imaging (in monkey) demonstrated that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) readily crossed the blood brain barrier and accumulated in the regions rich in 5-HT transporter (frontal- and posterial cortex, striata). However, the low accumulation of the tracer in the thalamus (rat and monkey) as well as the comparable displacement of the tracer observed with both citalopram, a -HT re-uptake inhibitor and maprotiline, a norepinephrine re-uptake inhibitor (rat), indicate that 5-[(18)F]fluoro-6-nitroquipazine ([(18)F]-1d) does not have the suggested potential for PET imaging of the serotin transporter (SERT).

1995-10-01·Naunyn-Schmiedeberg's Archives of Pharmacology4区 · 医学

Stimulation of serotonin release in the rat brain cortex by activation of ionotropic glutamate receptors and its modulation via ?2-heteroreceptors

4区 · 医学

Article

作者: M. Göthert ; C. Böing ; V. Schmitz ; K. Fink

Rat brain cortex slices were used to study (1) the release of 5-hydroxytryptamine (5-HT) induced by activation of N-methyl-D-aspartate (NMDA) or non-NMDA receptors and (2) the alpha 2-adrenoceptor-mediated modulation of NMDA-evoked 5-HT release. Cortical slices were preincubated with [3H]5-HT in the presence of the selective noradrenaline uptake inhibitor, maprotiline (to avoid false labelling of noradrenergic axon terminals), and the superfused with solution containing the 5-HT reuptake inhibitor, 6-nitroquipazine. In slices superfused with Mg(2+)-free medium, NMDA and L-glutamate, in a concentration-dependent manner, elicited an overflow of tritium. The NMDA-evoked tritium overflow was abolished by omission of Ca2+ ions, almost completely suppressed by 1.2 mM Mg2+ and only partly (by about 60%) inhibited by tetrodotoxin. Dizocilpine (formerly MK-801), an antagonist at the phencyclidine site within the NMDA-gated channel, also decreased the NMDA-evoked overflow. The competitive NMDA receptor antagonist DL-(E)-2-amino-4-methyl-5-phosphono-3-pentanoic acid (CGP 37849) caused a parallel shift of the NMDA concentration-response curve to the right. The NMDA-induced tritium overflow was not affected by addition of exogenous glycine but was inhibited by 5,7-dichlorokynurenic acid, an antagonist at the glycine site of the NMDA receptor. Spermidine slightly increased the NMDA-induced tritium overflow whereas arcaine, an antagonist at the polyamine site of the NMDA-receptor, caused a decrease. Ifenprodil and eliprodil, which exhibit different affinities for NMDA receptors composed of different subunits were highly potent (in the nanomolar range) in inhibiting the NMDA-evoked tritium overflow. Noradrenaline reduced, whereas the alpha 2-adrenoceptor antagonist idazoxan facilitated, the NMDA-evoked overflow. Idazoxan shifted the concentration-response curve of noradrenaline to the right. In slices superfused with solution containing 1.2 mM Mg2+, kainic acid or (RS)-alpha-amino-3-hydroxy-5-methyl-4 -isoxazole propionic acid (AMPA) also caused a concentration-dependent overflow of tritium, which again was not completely (by about 75 and 50%, respectively) inhibited by tetrodotoxin. The kainate-evoked tritium overflow was inhibited by the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) but not affected by CGP 37849 or arcaine. The AMPA-evoked tritium overflow was also decreased by CNQX. It is concluded that activation of NMDA or non-NMDA receptors elicits a release of 5-HT in the rat brain cortex. The receptors are at least partly located on the serotoninergic nerve terminals. The results with ifenprodil and eliprodil are compatible with the view that the NMDA receptor involved contains the NR2B subunit. The NMDA-evoked 5-HT release is modulated by presynaptic alpha 2-adrenoceptors.

1985-01-01·Arzneimittel-Forschung

Gabapentin decreases monoamine release without affecting acetylcholine release in the brain.

Article

作者: Reimann, W ; Göthert, M ; Schlicker, E

Superfused rat brain cortex slices preincubated with 3H-noradrenaline or 3H-serotonin and superfused rabbit caudate nucleus slices preincubated with 3H-choline were used to examine the effects of gabapentin (an amino acid chemically related to gamma-aminobutyric acid, GABA) on the electrically evoked 3H overflow. Gabapentin inhibited the electrically (3 Hz) evoked 3H overflow from slices preincubated with the 3H-monoamines in a concentration-dependent manner (at 1 mmol/l by 20-30%), but did not affect the evoked overflow from slices preincubated with 3H-choline. The following drugs did not modify the inhibitory effects of gabapentin: bicuculline, RS-baclofen, GABA, phentolamine, metitepin, cocaine, and the inhibitor of serotonin uptake, 6-nitroquipazine. Gabapentin did not modify the inhibitory effect of GABA on the evoked 3H overflow from slices preincubated with 3H-serotonin. In slices preincubated with 3H-noradrenaline the inhibitory effect of gabapentin was still observed when the stimulation frequency was 10 instead of 3 Hz. In conclusion, gabapentin mimics GABAB receptor activation, but it appears to act by a GABA receptor-independent, as yet unidentified mechanism.

100 项与 6-nitroquipazine 相关的药物交易

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