Imidazoline binding sites in Huntington's and Parkinson's disease putamen

doi:10.1016/0014-2999(96)00196-3

European Journal of Pharmacology

Volume 301, Issues 1–3, 22 April 1996, Pages R19-R21

https://doi.org/10.1016/0014-2999(96)00196-3 Get rights and content

Abstract

Binding of [³H]2-(2-benzofuranyl)-2-imidazoline ([³H]BFI) to the imidazoline I₂ receptor was determined in putamen taken post mortem from patients with two extrapyramidal motor disorders, Parkinson's and Huntington's diseases, and age-matched control subjects. No deficit of binding was apparent in Parkinson's disease, indicating that the receptors are not present on nigrostriatal terminals. A significant loss (by 56%) in imidazoline I₂ receptor binding was observed in Huntington's disease, consistent with the receptors being sited on degenerating neurons.

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New PET radiopharmaceuticals for imaging CNS diseases
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Positron emission tomography (PET) radiopharmaceuticals for central nervous system (CNS) diseases must fulfil prerequisites and pass clinical evaluations before they enter widespread use in humans. This article aims to give an overview on CNS PET ligands that after pre-clinical development have been applied in humans in recent years. The selected tracers have shown to provide reliable in vivo quantification of the respective molecular target and have been evaluated in at least one group of patients. The first target is the synaptic vesicle protein 2 A (SV2A), a marker for in vivo measurement of synaptic density, which can provide novel insights in the pathology of CNS disorders. Changes of synaptic density have been shown in several neurologic disorders and psychiatric conditions using the SV2A radioligand [¹¹C]UCB-J. The second group of radioligands include second-generation tracers for imaging tau aggregates (e.g., [¹⁸F]MK-6240 and [¹⁸F]PI-2620). These tau tracers display lower off-target binding and improved imaging properties allowing simplified acquisition protocols. PET radioligands for SV2A and tau aggregates are potential imaging markers for clinical trials and can also become part of routine patient care in the future. Furthermore, radioligands targeting phosphodiesterase 10A (e.g., [¹⁸F]MNI-659) have shown to provide reliable assessment of striatal pathology in Huntington's disease gene expansion carries, already at pre-manifest stages. Beyond these, new radioligands for the evaluation of mitochondrial activity ([¹⁸F]BCPP-EF), activated astroglia ([¹¹C]BU99008), and the purinoceptor P2X₇R as marker of neuroinflammation (e.g., [¹¹C]JNJ-717) have emerged. First evaluations of patients with neurodegenerative diseases yielded encouraging results, though non-invasive and simplified quantification methods might not be feasible or need confirmation in larger samples and more patient groups.
Agmatine reverses memory deficits induced by Aβ<inf>1</inf><inf>–</inf><inf>42</inf> peptide in mice: A key role of imidazoline receptors
2020, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Chronic administration of agmatine, moxonidine, and 2-BFI showed a significant decrease in escape latency during the acquisition and increase in time spent in the target quadrant, number of entries in platform quadrant and number of crossings over a platform during probe trial in MWM when compared with that of vehicle-treated mice. Altered densities of imidazoline receptor binding sites in psychiatric conditions such as depression and addiction, along with neurodegenerative disorders such as AD and Huntington's disease (HD) have been reported (Finn et al., 2003; Garcıia-Sevilla et al., 1998; Reynolds et al., 1996; Sastre and Garcia Sevilla, 1996). Moxonidine is an imidazoline compound with selective agonistic activity at I1-imidazoline receptor (Masajtis-Zagajewska et al., 2010).
Agmatine is a biogenic amine synthesized following decarboxylation of L-arginine by the enzyme arginine decarboxylase and exhibits favourable outcome in neurodegenerative disorders. Present study was designed to examine the relationship between agmatine and the imidazoline receptors in memory deficits induced by Aβ₁_–₄₂ peptide in mice. Mice were treated with single intracerebroventricular (i.c.v.) injection of Aβ₁_–₄₂ peptide (3 μg) and evaluated for learning and memory in Morris water maze (MWM) and subjected to Aβ₁_–_42, TNF-α and IL-6 and BDNF immunocontent analysis within the hippocampus. While the learning and memory impairment was evident in the mice subjected to MWM test following Aβ₁_–₄₂ peptide administration, there was a significant increase in Aβ₁_–_42, TNF-α and IL-6 and reduction in BDNF immunocontent within the hippocampus. Daily intraperitoneal (i.p.) treatment with agmatine (10 and 20 mg/kg); imidazoline I₁ receptor agonist, moxonidine and imidazoline I₂ receptor agonist, 2-BFI starting from day 8 to 27 post-Aβ₁_–₄₂ injection, significantly prevented the cognitive deficits and normalized the Aβ₁_–₄₂ peptide, IL-6, TNF-α and BDNF immunocontent in hippocampus. On the other hand, pre-treatment with imidazoline I₁ receptor antagonist, efaroxan and imidazoline I₂ receptor antagonist, BU 224 attenuated the effects of agmatine on learning and memory in MWM, IL-6, TNF-α and BDNF content. In conclusion, the present study provides functional evidence for the involvement of the imidazoline receptors in agmatine induced reversal of Aβ₁_–₄₂ induced memory deficits in mice. The data projects agmatine and imidazoline receptor agonists as a potential therapeutic target for the treatment of AD.
Molecular Imaging in Huntington's Disease
2018, International Review of Neurobiology
Citation Excerpt :
These findings suggest that quantification of I2BS could be a useful marker of astrocytes activation in conditions characterized by marked gliosis. Post-mortem studies in HD brains, demonstrated loss of up to 56% in I2BS receptor binding in the putamen (Reynolds, Boulton, Pearson, Hudson, & Nutt, 1996). Therefore, suggesting I2BS receptors are present on striatal GABAergic neurons that degenerate in HD.
Huntington's disease (HD) is a rare monogenic neurodegenerative disorder caused by a trinucleotide CAG repeat expansion in the huntingtin gene resulting in the formation of intranuclear inclusions of mutated huntingtin. The accumulation of mutated huntingtin leads to loss of GABAergic medium spiny neurons (MSNs); subsequently resulting in the development of chorea, cognitive dysfunction and psychiatric symptoms. Premanifest HD gene expansion carriers, provide a unique cohort to examine very early molecular changes, occurring before the development of overt symptoms, to elucidate disease pathophysiology and identify reliable biomarkers of HD progression. Positron emission tomography (PET) is a non-invasive molecular imaging technique allowing the evaluation of specific molecular targets in vivo. Selective PET radioligands provide invaluable tools to investigate the role of the dopaminergic system, brain metabolism, microglial activation, phosphodiesterase 10A, and cannabinoid, GABA, adenosine and opioid receptors in HD. PET has been employed to monitor disease progression aiming to identify a reliable biomarker to predict phenoconversion from premanifest to manifest HD.
A useful PET probe [11C]BU99008 with ultra-high specific radioactivity for small animal PET imaging of I<inf>2</inf>-imidazoline receptors in the hypothalamus
2017, Nuclear Medicine and Biology
Citation Excerpt :
IRs are widely distributed throughout the tissues of various species including humans, and are present in the central and peripheral nervous systems and in various organs such as the kidney, lung, and heart [14]. Additionally, I2Rs have been linked to several central nervous system disorders [15–24]. Additionally, I2R has been found in the hypothalamus [25,26], and it has reported that selective I2R ligands promoted food intake [27,28], which is presumed to be an effect of eating function through the hypothalamus known as a feeding center [29].
A positron emission tomography (PET) probe with ultra-high specific radioactivity (SA) enables measuring high receptor specific binding in brain regions by avoiding mass effect of the PET probe itself. It has been reported that PET probe with ultra-high SA can detect small change caused by endogenous or exogenous ligand. Recently, Kealey et al. developed [¹¹C]BU99008, a more potent PET probe for I₂-imidazoline receptors (I₂Rs) imaging, with a conventional SA (mean 76 GBq/μmol) showed higher specific binding in the brain. Here, to detect small change of specific binding for I₂Rs caused by endogenous or exogenous ligand in an extremely small region, such as hypothalamus in the brain, we synthesized and evaluated [¹¹C]BU99008 with ultra-high SA as a useful PET probe for small-animal PET imaging of I₂Rs.
[¹¹C]BU99008 was prepared by [¹¹C]methylation of N-desmethyl precursor with [¹¹C]methyl iodide. Biodistribution, metabolite analysis, and brain PET studies were conducted in rats.
[¹¹C]BU99008 with ultra-high SA in the range of 5400–16,600 GBq/μmol were successfully synthesized (n = 7), and had appropriate radioactivity for in vivo study. In the biodistribution study, the mean radioactivity levels in all investigated tissues except for the kidney did not show significant difference between [¹¹C]BU99008 with ultra-high SA and that with conventional SA. In the metabolite analysis, the percentage of unchanged [¹¹C]BU99008 at 30 min after the injection of probes with ultra-high and conventional SA was similar in rat brain and plasma. In the PET study of rats' brain, radioactivity level (AUC_{30–60 min}) in the hypothalamus of rats injected with [¹¹C]BU99008 with ultra-high SA (64 [SUV ∙ min]) was significantly higher than that observed for that with conventional SA (50 [SUV ∙ min]). The specific binding of [¹¹C]BU99008 with ultra-high SA (86% of total binding) for I₂R was higher than that of conventional SA (76% of total binding).
A PET study using [¹¹C]BU99008 with ultra-high SA would thus contribute to the detection of small changes in or small regions with I₂R expression and hence may be useful in elucidating new functions of I₂R.
Biological profile and bioavailability of imidazoline compounds on morphine tolerance modulation
2015, European Journal of Pharmacology
Citation Excerpt :
To overcome the side effects of opiate drugs, the synergism with compounds interacting with imidazoline I2 receptors has been reported (Dardonville and Rozas, 2004). The imidazoline receptor family includes I1 receptors regulating cardiovascular function, I2 involved in central nervous system pathologies such as Parkinson's disease, depression, tolerance and addiction to opioids, and I3 representing a potential target for the treatment of diabetes (Dardonville and Rozas, 2004; Nikolic and Agbaba, 2012; Reynolds et al., 1996; Ruiz-Durántez et al., 2003). Moreover, I2 receptors are present in brain areas involved in perception and response to painful stimuli (Ruggiero et al., 1998).
Tolerance to opioid administration represents a serious medical alert in different chronic conditions. This study compares the effects of the imidazoline compounds 1, 2, and 3 on morphine tolerance in an animal model of inflammatory pain in the rat. 1, 2, and 3 have been selected in that, although bearing a common scaffold, preferentially bind to α₂-adrenoceptors, imidazoline I₂ receptors, or both systems, respectively. Such compounds have been tested in vivo by measuring the paw withdrawal threshold to mechanical pressure after complete Freund's adjuvant injection. To determine the ligand levels in rat plasma, an HPLC-mass spectrometry method has been developed. All the compounds significantly reduced the induction of morphine tolerance, showing different potency and duration of action. Indeed, the selective imidazoline I₂ receptor interaction (2) restored the analgesic response by maintaining the same time-dependent profile observed after a single morphine administration. Differently, the selective α_2C-adrenoceptor activation (1) or the combination between α_2C-adrenoceptor activation and imidazoline I₂ receptor engagement (3) promoted a change in the temporal profile of morphine analgesia by maintaining a mild but long lasting analgesic effect. Interestingly, the kinetics of compounds in rat plasma supported the pharmacodynamic data. Therefore, this study highlights that both peculiar biological profile and bioavailability of such ligands complement each other to modulate the reduction of morphine tolerance. Based on these observations, 1–3 can be considered useful leads in the design of new drugs able to turn off the undesired tolerance induced by opioids.
In vivo evaluation of a new 18F-labeled PET ligand, [18F]FEBU, for the imaging of I<inf>2</inf>-imidazoline receptors
2015, Nuclear Medicine and Biology
Citation Excerpt :
IRs have a broad tissue distribution in various species including humans, and are present in the central nervous systems (CNS) and in peripheral organs such as the kidneys, lungs, and heart [9]. Functions associated with I2Rs are not known, but evidence exists for their involvement in various CNS disorders, such as depression [10,11], Alzheimer's disease [12], Huntington's disease [13], Parkinson's disease [14], aging [15], and glial cell tumors [16]. It is possible that the changes in I2R density are directly or indirectly related with a particular disease.
The functions of I₂-imidazoline receptors (I₂Rs) are unknown, but evidence exists for their involvement in various neuropsychiatric disorders. Although a few positron emission tomography (PET) I₂R ligands have been developed, of which [¹¹C]FTIMD and [¹¹C]BU99008 were evaluated as PET I₂R imaging ligands in monkeys, no human PET imaging study using an I₂R-selective PET ligand has been conducted yet. Thus, we synthesized an ¹⁸F-labeled I₂R-selective ligand (BU99018 or FEBU, Ki for I₂Rs = 2.6 nM), and evaluated its application using rodents in PET imaging in vivo toward the development of a clinically-useful I₂R PET imaging ligand.
[¹⁸F]FEBU was synthesized by the reaction of its precursor and [¹⁸F]fluoroethyl bromide. A biodistribution and brain PET study were conducted in mice and rats respectively.
[¹⁸F]FEBU was successfully synthesized yielding a radioactivity suitable for injection (10.1 ± 5.3% at the end of the irradiation (n = 10) based on ¹⁸F⁻). The specific activity at end of synthesis (EOS) was 40–147 TBq/mmol (n = 10). The radiochemical purity was > 99% at EOS and remained > 99% for 90 min after EOS. In mice brain uptake was relatively high. In the blocking study with the co-injection of the high-affinity I₂R ligand BU224 (1 mg/kg b.w.) brain uptake was significantly decreased 30 min post-injection. In the PET studies the radioactivity was highly accumulated in the I₂R-rich hypothalamus. Pretreatment with BU224 (1 mg/kg b.w.) significantly decreased the radioactivity in the hypothalamus to 23% of that of the control from 60 to 90 min post-injection.
[¹⁸F]FEBU was sufficiently stable as a PET ligand and had a relatively high specific binding affinity for I₂Rs in rats and mice.

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European Journal of Pharmacology

Abstract

References (8)

Autoradiographic distribution of alpha2 adrenoceptors, NAIBS and 5-HT1A receptors in human brain using [³H]idazoxan and [³H]rauwolscine

Brain Res.

Immunodetection of putative imidazoline receptor proteins in the human and rat brain and other tissues

Neurosci. Lett.

Dementia in Huntington's disease is associated with neurochemical deficits in the caudate nucleus not the cerebral cortex

Neurosci. Lett.

Verteilung des 5-Hydroxytryptamins (Serotonin) on Gehirn des Menschen und sein Verhalte, bei Patienten mit Parkinson Syndrom

Klin. Wschr.

Cited by (46)

New PET radiopharmaceuticals for imaging CNS diseases

Agmatine reverses memory deficits induced by Aβ<inf>1</inf><inf>–</inf><inf>42</inf> peptide in mice: A key role of imidazoline receptors

Molecular Imaging in Huntington's Disease

A useful PET probe [<sup>11</sup>C]BU99008 with ultra-high specific radioactivity for small animal PET imaging of I<inf>2</inf>-imidazoline receptors in the hypothalamus

Biological profile and bioavailability of imidazoline compounds on morphine tolerance modulation

In vivo evaluation of a new <sup>18</sup>F-labeled PET ligand, [<sup>18</sup>F]FEBU, for the imaging of I<inf>2</inf>-imidazoline receptors

Rapid communicationImidazoline binding sites in Huntington's and Parkinson's disease putamen

Abstract

Brain Res.

Neurosci. Lett.

Neurosci. Lett.

Verteilung des 5-Hydroxytryptamins (Serotonin) on Gehirn des Menschen und sein Verhalte, bei Patienten mit Parkinson Syndrom

Klin. Wschr.

Rapid communication
Imidazoline binding sites in Huntington's and Parkinson's disease putamen