Synthesis and Pharmacological Characterization of [125I]Iodomethyllycaconitine ([125I]Iodo-MLA). A New Ligand for the α7Nicotinic Acetylcholine Receptor

Navarro, Hernán A.; Zhong, Desong; Abraham, Philip; Xu, Heng; Carroll, F. Ivy

doi:10.1021/jm990544f

Cited by 30 publications

(22 citation statements)

References 27 publications

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“…Of note, MLA from 5 to 20 µM alone did not have any significant anti-proliferative effect on SH-SY5Y cells. MLA is a relatively small reversible-binding compound that can easily across the blood-brain barrier in vivo [37], [38]. Considering the low cytotoxicity and the ability to pass the blood-brain barrier, MLA may be a potent drug in the treatment of AD.…”

Section: Discussionmentioning

confidence: 99%

Methyllycaconitine Alleviates Amyloid-β Peptides-Induced Cytotoxicity in SH-SY5Y Cells

et al. 2014

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Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder. As the most common form of dementia, it affects more than 35 million people worldwide and is increasing. Excessive extracellular deposition of amyloid-β peptide (Aβ) is a pathologic feature of AD. Accumulating evidence indicates that macroautophagy is involved in the pathogenesis of AD, but its exact role is still unclear. Although major findings on the molecular mechanisms have been reported, there are still no effective treatments to prevent, halt, or reverse Alzheimer's disease. In this study, we investigated whether Aβ25–35 could trigger an autophagy process and inhibit the growth of SH-SY5Y cells. Furthermore, we examined the effect of methyllycaconitine (MLA) on the cytotoxity of Aβ25–35. MLA had a protective effect against cytotoxity of Aβ, which may be related to its inhibition of Aβ-induced autophagy and the involvement of the mammalian target of rapamycin pathway. Moreover, MLA had a good safety profile. MLA treatment may be a promising therapeutic tool for AD.

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Section: Discussionmentioning

confidence: 99%

Methyllycaconitine Alleviates Amyloid-β Peptides-Induced Cytotoxicity in SH-SY5Y Cells

et al. 2014

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“…Both radioligands have been widely used for studying α7 nAChRs in vitro due to their binding α7 nAChRs irreversibly and selectively in the brain [28], [29]. In our binding studies, the Kd values for 125 I-CHIBA-1001 binding showed slightly lower overall affinity in rat brain homogenates compared to 125 I-α-bungarotoxin [30] and 125 I-MLA [27] (Kd = 70 nM vs. 1.5 and 1.8 nM, respectively), however, the Bmax values were in general agreement with the corresponding values determined by both of the above ligands (Bmax = 73 fmol/mg protein vs. 63 and 68 fmol/mg protein, respectively). These results suggest that 125 I-CHIBA-1001 binding might be similar to 125 I-α-bungarotoxin binding or 125 I-MLA binding to α7 nAChRs in the brain of rats.…”

Section: Discussionmentioning

confidence: 65%

“…[ 125 I]α-bungar-otoxin [25], [26] and [ 125 I]methyllycaconitine ([ 125 I]MLA) [27] are well known for researchers who pursued the development of radioligands for α7 nAChRs. Both radioligands have been widely used for studying α7 nAChRs in vitro due to their binding α7 nAChRs irreversibly and selectively in the brain [28], [29].…”

Section: Discussionmentioning

confidence: 99%

An Experimental Study on 131I-CHIBA-1001: A Radioligand for α7 Nicotinic Acetylcholine Receptors

Liu

Zhao

et al. 2013

PLoS ONE

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ObjectiveThe α7 nicotinic acetylcholine receptors (nAChRs) play a vital role in the pathophysiology of neuropsychiatric diseases such as Alzheimer’s disease and depression. However, there is currently no suitable positron emission tomography (PET) or Single-Photon Emission Computed Tomography (SPECT) radioligands for imaging α7 nAChRs in brain. Here our aim is to radiosynthesize a novel SPECT radioligand 131I-CHIBA-1001 for whole body biodistribution study and in vivo imaging of α7 nAChRs in brain.Method 131I-CHIBA-1001 was radiosynthesized by chloramine-T method. Different conditions of reaction time and temperature were tested to get a better radiolabeling yield. Radiolabeling yield and radiochemical purities of 131I-CHIBA-1001 were analyzed by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) system. Whole body biodistribution study was performed at different time points post injection of 131I-CHIBA-1001 in KM mice. Monkey subject was used for in vivo SPECT imaging in brain.ResultThe radiolabeling yield of 131I-CHIBA-1001 reached 96% within 1.5∼2.0 h at 90∼95°C. The radiochemical purity reached more than 99% after HPLC purification. 131I-CHIBA-1001 was highly stable in saline and fresh human serum in room temperature and 37°C separately. The biodistribution data of brain at 15, 30, and 60 min were 11.05±1.04%ID/g, 8.8±0.04%ID/g and 6.28±1.13%ID/g, respectively. In experimental SPECT imaging, the distribution of radioactivity in the brain regions was paralleled with the distribution of α7 nAChRs in the monkey brain. Moreover, in the blocking SPECT imaging study, the selective α7 nAChR agonist SSR180711 blocked the radioactive uptake in the brain successfully.ConclusionThe CHIBA-1001 can be successfully radiolabeled with 131I using the chloramine-T method. 131I-CHIBA-1001 can successfully accumulate in the monkey brain and image the α7 acetylcholine receptors. 131I-CHIBA-1001 can be a candidate for imagingα7 acetylcholine receptors, which will be of great value for the diagnosis and treatment of mental diseases.

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“…The α-bungarotoxin and MLA are well known as specific α7 nAChR antagonists. However, due to their large molecular weights, they have difficulty in passing through the BBB, which makes them poor radioligands (Davies et al, 1999;James et al, 1980;Navarro et al, 2000). A radiolabeled antagonist for α7 nAChR with a sufficiently high affinity for in vivo imaging is yet to be identified.…”

Section: α7 Nachr Ligandsmentioning

confidence: 99%

Human Brain Imaging of Acetylcholine Receptors

Toyohara

Sakata

Ishiwata

2014

Imaging of the Human Brain in Health and Disease

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Synthesis and Pharmacological Characterization of [¹²⁵I]Iodomethyllycaconitine ([¹²⁵I]Iodo-MLA). A New Ligand for the α₇Nicotinic Acetylcholine Receptor

Cited by 30 publications

References 27 publications

Methyllycaconitine Alleviates Amyloid-β Peptides-Induced Cytotoxicity in SH-SY5Y Cells

Methyllycaconitine Alleviates Amyloid-β Peptides-Induced Cytotoxicity in SH-SY5Y Cells

An Experimental Study on 131I-CHIBA-1001: A Radioligand for α7 Nicotinic Acetylcholine Receptors

Human Brain Imaging of Acetylcholine Receptors

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