Synthesis and biological evaluation of novel radioiodinated imidazopyridine derivatives for amyloid-β imaging in Alzheimer’s disease

doi:10.1016/j.bmc.2014.05.043

Bioorganic & Medicinal Chemistry

Volume 22, Issue 15, 1 August 2014, Pages 4189-4197

https://doi.org/10.1016/j.bmc.2014.05.043 Get rights and content

Abstract

Non-invasive detection for amyloid-β peptide (Aβ) deposition has important significance for the early diagnosis and medical intervention for Alzheimer’s disease (AD). In this study, we developed a series of imidazopyridine derivatives as potential imaging agents for single-photon emission computed tomography (SPECT). Two of them, compounds DRK092 and DRM106, showed higher affinity for synthetic human Aβ 1–40 fibrils than did the well-known amyloid-imaging agent IMPY. A metabolite analysis revealed brain-permeable radioactive metabolites of ¹²⁵I-labeled DRK092 and IMPY; no radioactive metabolites from ¹²⁵I-labeled DRM106 ([¹²⁵I]DRM106) were detected. In addition, in vitro autoradiography clearly demonstrated specific binding of [¹²⁵I]DRM106 in the hippocampal region of AD enriched with Aβ plaques. Thus, our results strongly suggested that compound DRM106 can be used as an imaging agent for SPECT to detect Aβ deposition in AD brain.

Graphical abstract

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the appearance of amyloid-β peptide (Aβ) plaques and neurofibrillary tangles (NFTs). Since fibrillary Aβ can accumulate in the brain for decades before the appearance of AD,¹ in-vivo non-invasive detection of Aβ deposition is crucial for the early diagnosis and treatment of AD at the prodromal stage. Nuclear imaging by positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are clinically applicable for functional examination, and are widely used in translational research. Amyloid imaging with PET tracers has been successfully employed in preclinical research and clinical trials.2, 3, 4, 5 ¹¹C-labeled Pittsburgh compound B ([¹¹C]PiB) is a widely used PET ligand that has been employed to quantitatively detect amyloid deposition in AD model animals and patients.2, 3, 6 It has also been used as an imaging biomarker for AD diagnosis as well as a prognostic index for the conversion from mild cognitive impairment (MCI) to AD.7, 8, 9 To overcome the disadvantage of the short half-life (approximately 20 min) of ¹¹C-labeled tracers, ligands labeled with ¹⁸F (half-life: approximately 110 min) have also been developed for routine medical needs.5, 10, 11, 12 Two such radioligands, [¹⁸F]florbetapir and [¹⁸F]flutemetamol, have already been approved by the US Food and Drug Administration (FDA) as radioactive diagnostic agents to detect amyloid deposition in adult patients with cognitive impairment.

In comparison with PET, radioisotopes used in SPECT, such as ¹²³I (half-life: 13.22 h), have a longer half-life and can therefore achieve a longer distance delivery. More SPECT scanners have also been installed for routine clinical examination. Although inferior to PET in terms of sensitivity and quantitative performance, SPECT is more suitable for the primary screening of prodromal AD patients, owing to lower operating and installation costs. In the past decade, several SPECT ligands with different scaffolds have been developed that can be used to successfully visualize amyloid deposition in brain sections of AD models and patients with AD in vitro. To date, however, there has been lack of SPECT ligands available for amyloid imaging to distinguish between normal subjects and patients with AD. In the present study, we developed a series of novel imidazopyridine derivatives to be employed as SPECT agents in the in vivo detection of Aβ pathology.

Section snippets

Results and discussion

To date, a number of iodinated ligands, such as dipheny-1,3,4-oxadiazole (1,3,4-DPOD) derivatives,¹³ aurone derivatives,¹⁴ 1,4-diphenyltriazole derivatives,¹⁵ pyridyl benzofuran derivatives,¹⁶ and imidazo[1,2-a]pyridine derivatives,¹⁷ have been employed for amyloid imaging with SPECT (Fig. 1). IMPY, an imidazo[1,2-a]pyridine derivative, is the only ligand for SPECT that has been tested in human subjects.¹⁸ Although this ligand has shown excellent properties as an imaging probe in preclinical

Conclusion

In the present study, we synthesized a series of novel imidazopyridine derivatives with a chemical structure similar to that of IMPY. We obtained a promising compound (DRM106) with excellent brain permeability and a rapid off-target washout, a sufficient affinity to Aβ aggregate, and an ideal metabolic stability. These data strongly suggest that DRM106, labeled with iodine-123, can be efficiently employed as SPECT agent for the detection of the amyloid pathology in the brains of patients with

Experiments

Melting points (mp) were measured using a micromelting point apparatus (MP-500P, Yanaco, Tokyo, Japan). ¹H and ¹³C NMR spectra were recorded on a JNM-AL-400 spectrometer (JEOL; Tokyo, Japan) using tetramethylsilane as an internal standard. All chemical shifts (δ) were reported in parts per million (ppm) downfield from the standard. High-resolution (HR) fast atom bombardment–mass spectrometry (FAB–MS) was performed using a JEOL NMS-SX102 spectrometer (JEOL). Column chromatography was performed

Acknowledgments

The authors thank Prof. John Q. Trojanowski and Prof. Virginia M.-Y. Lee (Center for Neurodegenerative Disease Research, University of Pennsylvania) for kindly providing human tissue. This work was supported in part by Grants-in-Aid for Japan Advanced Molecular Imaging Program and Core Research for Evolutional Science and Technology (T.S.), and Scientific Research on Innovative Areas (‘Brain Environment’) 23111009 (M.H.) from the Ministry of Education, Culture, Sports, Science and Technology,

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^†: Co-corresponding author: The United Graduate School of Veterinary Science, Gifu University, 1-1 Yanagido, Gifu City 501-1193, Japan. Tel.: +81 155 49 5395; fax: +81 155 49 5398.

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Synthesis and biological evaluation of novel radioiodinated imidazopyridine derivatives for amyloid-β imaging in Alzheimer’s disease

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusion

Experiments

Acknowledgments

Nucl. Med. Biol.

Prog. Neurobiol.

Bioorg. Med. Chem.

Brain Res.

J. Chromatogr. B

Acta Neuropathol. (Berl)

J. Neurosci.

Ann. Neurol.

Eur. J. Nucl. Med. Mol. Imaging

J. Nucl. Med.

Brain

Brain