Development and Preliminary Evaluation of a ¹²⁵I-Labeled Radioligand ([¹²⁵I]iodotrazoline) for In Vitro Detection of Imidazoline-2 Binding Site in the Brain

Article

作者: Guo, Yiming ; Huang, Donglan ; Cui, Mengchao ; Fu, Hualong

Astrocytes exert multiple functions within the brain, including regulating neuroinflammation and maintaining homeostasis, and the reactive astrocytes are implicated in many neurodegenerative disorders. Imidazoline-2 binding site (I₂BS) has been established as a reliable biomarker for precisely quantifying reactive astrocytes. Here, we reported the development of [¹²⁵I]iodotrazoline ([¹²⁵I]8), a novel I₂BS radioligand with high affinity (K_i = 6.8 nM) and exceptional selectivity over α₂-adrenoceptors (>1400 folds). In vitro autoradiography (ARG) using rat brain sections revealed a heterogeneous distribution of [¹²⁵I]8, with high signals in the medulla, midbrain, pons, and hypothalamus. Pretreatment with unlabeled I₂BS-selective ligands, BU224 and FTIMD, reduced the binding by >30%, indicating high in vitro specificity for I₂BS. Ex vivo ARG results confirmed this distribution pattern in the rat brain. Biodistribution results in mice demonstrated a rapid brain uptake of [¹²⁵I]8 (3.35% ID/g at 2 min postinjection) with slow washout. Metabolite analysis exhibited the desirable biostability of [¹²⁵I]8 in the rat brain. Altogether, this work provides a new ¹²⁵I-labeled radioligand featuring a novel 2-trans-styryl-imidazoline scaffold, which shows significant specificity binding for I₂BS in vitro, serving as a valuable tool for I₂BS detection and astrocyte-related pathology research.

2024-03-01·Psychopharmacology

The imidazoline I2 receptor agonist 2-BFI reduces abuse-related effects of morphine: self-administration and drug discrimination

Article

作者: Zhang, Yanan ; Siemian, Justin N ; Liu, David H ; Li, Jun-Xu ; Woodhouse, Kristen

RATIONALEIncreasing evidence shows that imidazoline I₂ receptor agonists enhance opioid-induced analgesia, suggesting that the combination of I₂ receptor agonists with opioids could be a favorable strategy for pain control. However, the effect of I₂ receptor agonists on the abuse liability of opioids is unknown. This study examined the impact of the I₂ receptor agonist 2-BFI on some abuse-related behavioral effects of the opioid morphine in rats.OBJECTIVESThe von Frey filament test was used to determine the antinociceptive effects of 2-BFI (intravenous, i.v.) in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. IV self-administration was used to assess the reinforcing effects of 2-BFI alone and to assess the effects of non-contingent injections of 2-BFI (i.p.) on morphine self-administration. A two-lever drug discrimination paradigm in which rats were trained to discriminate 3.2 mg/kg morphine (i.p.) from saline was used to examine whether 2-BFI or another I₂ receptor agonist 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride (BU224) affected the discriminative stimulus effects of morphine.RESULTS2-BFI could not maintain reliable self-administration behavior in rats with no pain or CFA-treated inflammatory pain. However, pretreatment with 2-BFI (i.p.) produced dose-dependent decreases in the dose-effect curve of morphine self-administration. Both 2-BFI and BU224 did not substitute for morphine but significantly attenuated the discriminative stimulus effects of morphine.CONCLUSIONSThese results suggest that I₂ receptor agonists do not enhance, but in fact appear to decrease, the abuse liability of opioids, further supporting the potential utility of I₂ receptor agonist-opioid combination therapy for pain control.

2021-10-01·Molecular Psychiatry1区 · 医学

Astroglial tracer BU99008 detects multiple binding sites in Alzheimer’s disease brain

1区 · 医学

Article

作者: Koistinen, Niina A ; Malarte, Mona-Lisa ; Kumar, Amit ; Nordberg, Agneta ; Lemoine, Laetitia ; Nennesmo, Inger ; Ghetti, Bernardino ; Ingelsson, Martin

AbstractWith reactive astrogliosis being established as one of the hallmarks of Alzheimer’s disease (AD), there is high interest in developing novel positron emission tomography (PET) tracers to detect early astrocyte reactivity. BU99008, a novel astrocytic PET ligand targeting imidazoline-2 binding sites (I2BS) on astrocytes, might be a suitable candidate. Here we demonstrate for the first time that BU99008 could visualise reactive astrogliosis in postmortem AD brains and propose a multiple binding site [Super-high-affinity (SH), High-affinity (HA) and Low-affinity (LA)] model for BU99008, I2BS specific ligands (2-BFI and BU224) and deprenyl in AD and control (CN) brains. The proportion (%) and affinities of these sites varied significantly between the BU99008, 2-BFI, BU224 and deprenyl in AD and CN brains. Regional binding studies demonstrated significantly higher 3H-BU99008 binding in AD brain regions compared to CN. Comparative autoradiography studies reinforced these findings, showing higher specific binding for 3H-BU99008 than 3H-Deprenyl in sporadic AD brain compared to CN, implying that they might have different targets. The data clearly shows that BU99008 could detect I2BS expressing reactive astrocytes with good selectivity and specificity and hence be a potential attractive clinical astrocytic PET tracer for gaining further insight into the role of reactive astrogliosis in AD.

100 项与 BU-224 相关的药物交易

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