Elsevier

Bioorganic & Medicinal Chemistry

Volume 24, Issue 21, 1 November 2016, Pages 5148-5157
Bioorganic & Medicinal Chemistry

Blood–brain barrier permeability of ginkgolide: Comparison of the behavior of PET probes 7α-[18F]fluoro- and 10-O-p-[11C]methylbenzyl ginkgolide B in monkey and rat brains

https://doi.org/10.1016/j.bmc.2016.08.032Get rights and content

Abstract

The blood–brain barrier permeability of ginkgolide B was examined using positron emission tomography (PET) probes of a 18F-incorporated ginkgolide B ([18F]-2) and a 11C-incorporated methylbenzyl-substituted ginkgolide B ([11C]-3). PET studies in monkeys showed low uptake of [18F]-2 into the brain, but small amounts of [11C]-3 were accumulated in the parenchyma. Furthermore, when cyclosporine A was preadministered to rats, the accumulation of [18F]-2 in the rat brain did not significantly change, however, the accumulation of [11C]-3 was five times higher than that in the control rat. These results provide effective approaches for investigating the drug potential of ginkgolides.

Introduction

Ginkgo biloba (G. biloba) extracts have been shown to have neuroprotective effects both in vivo and in vitro.1, 2, 3, 4, 5, 6 In some parts of Asia and in Western countries, the standardized G. biloba extracts (e.g., EGb 761) have been utilized as complementary medicines for the improvement of peripheral and cerebral blood flow, and treatment of cerebral insufficiencies, including Alzheimer’s disease.1, 2, 3, 4, 5, 6 G. biloba extracts are subdivided into two major groups, the flavone glycosides and the terpene lactones, which are thought to contribute to its vasotropic and neuroprotective effects. The most attractive components of the extract are ginkgolides (terpene lactones), which are believed to play an important role in the neuromodulatory effects of G. biloba. They have been shown to act as platelet-activating factor (PAF) receptor antagonists,7, 8, 9 glycine receptor antagonists,10, 11, 12, 13, 14 GABAA receptor antagonists,15, 16 5-HT3 receptor antagonists,17, 18 and inhibitors of neuronal cell death caused by β-amyloid aggregation.19, 20, 21, 22 However, the molecular mechanisms underlying the action of ginkgolides in the central nervous system (CNS) are poorly understood. In particular, determining whether ginkgolides can penetrate the blood–brain barrier (BBB) has been a challenge.23 In this regard, Nanjing group investigated the BBB permeability of ginkgolide B by an LC-MS/MS method.23 On the other hand, we speculated that in vivo imaging of ginkgolides, using nuclear medicine techniques such as positron emission tomography (PET), would provide valuable information and insights into the BBB permeability of these compounds, from the viewpoint of molecular biology. Here, we studied the BBB permeability in both rat and monkey brains using two PET probes derived from ginkgolide B (1), 7α-[18F]fluorine-substituted ginkgolide B ([18F]-2) and 10-O-p-[11C]methylbenzyl ginkgolide B ([11C]-3), the latter of which was efficiently synthesized using our rapid C-[11C]methylation methods.24, 25

Section snippets

General methods

1H and 13C nuclear magnetic resonance (NMR) spectra were recorded on a JEOL JNM α-400 or a JNM ECS-400 spectrometer. The proton chemical shifts are expressed in parts per million (ppm) downfield from tetramethylsilane (δ 0.00 and δ 0.00) or in ppm relative to CDCl3 (δ 7.24 and δ 77.0) in 1H and 13C NMR, respectively. The abbreviations s, d, t, q, and m signify singlet, doublet, triplet, quartet, and multiplet, respectively. High-resolution mass spectra (HRMS) were measured on JEOL JMS-700/GI.

Design and synthesis of ginkgolide probes with antagonist activity against the PAF receptor

To design a ginkgolide PET probe with BBB permeability, we focused on enhancing the hydrophobicity by introducing an alkyl substituent at the C(10) position of ginkgolide B (1), which has relatively high affinity for the PAF receptor.33, 34 It is believed that the PAF receptor is involved in several events in the CNS and that it is an important target for the neuromodulatory effects of ginkgolides.7, 8, 9 A hydroxyl group change at the C(10) position of the corresponding methyl ether did not

Conclusion

We evaluated the brain uptake and BBB permeability of ginkgolide B derivatives, both in vitro and in vivo. There was a slight but distinct brain uptake of 10-O-p-methylbenzylated ginkgolide B (3), whereas the uptake of 7α-fluorinated ginkgolide B (2) was miniscule at best, as determined by the in vivo imaging of the monkey brain and in vitro accumulation analysis in the rat brain using the [18F]-2 and [11C]-3 PET probes. Additionally, the cell-permeability analyses revealed that ginkgolide B (1

Acknowledgements

This work was supported in part by a Grant-in-Aid for Creative Scientific Research (No. 13NP0401) and Scientific Research (A) (25242070) from JSPS, and a consignment expense for the Molecular Imaging Program on ‘Research Base for Exploring New Drugs’ from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan. The authors would specially like to thank the scientific researchers of Hamamatsu Photonics K.K.: T. Kakiuchi, N. Harada, H. Ohba, H. Uchida, S. Nishiyama, D.

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