Syntheses and pharmacological characterization of novel thiazole derivatives as potential mGluR5 PET ligands
Graphical abstract
Introduction
Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate receptors form a large family, which can be classified into ionotropic and metabotropic glutamate receptors. The ligand-gated, cation-selective ion channels that form the ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission. IGluRs include kainate, α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors. Metabotropic glutamate receptors (mGluRs) are known to be involved in the modulation of iGluRs and appear to fine-tune neuronal activity. The subclass of mGluRs consists of eight G-protein coupled receptors (GPCRs) that are sub-divided according to their receptor pharmacology, amino acid sequences and their secondary messenger systems into three groups (groups I–III). Group I comprises mGluR1 and mGluR5 that are mainly post-synaptic receptors activating Gq proteins and phospholipase C as a secondary messenger. Group II consists of mGluR2 and mGluR3 while mGluR4, mGluR6, mGluR7, and mGluR8 form group III. Receptors of both groups use a Gi protein for signal transduction.1, 2
MGluRs have been implicated in numerous CNS disorders. Notably, mGluR5, which is predominantly located in the hippocampus, striatum, and cortex,3 was shown to be involved in neurodegenerative diseases such as Alzheimer’s disease,4, 5 Parkinson’s disease6, 7 or other disorders such as depression,8 anxiety,9 schizophrenia,10, 11 neuropathic pain,12, 13 drug addiction,14 and fragile X syndrome.15 However, the function of mGluR5 is not yet well understood and it is generally agreed that a better understanding of the physiological and pathophysiological roles of the receptor will open new avenues for the development of diagnostic tools and effective drugs for the above mentioned CNS disorders.16
Positron emission tomography (PET) is a non-invasive in vivo imaging technique that offers the possibility to visualize and analyze mGluR5 expression under various physiological and pathophysiological conditions. Our group reported the first successful in vivo imaging of mGluR5 in rodents and humans using carbon-11 labeled ABP688 (Figure 1, Figure 4, 4).17 The short physical half-life of carbon-11 (t1/2 = 20 min), however, does not permit the widespread use of [11C]-ABP688. More advantageous seems the use of fluorine-18 (t1/2 = 110 min) due to the possibility of satellite distribution of potential fluorine-18 labeled compounds to centers without a cyclotron facility. Recently, a number of fluorine-18 labeled compounds for imaging mGluR5 have been reported. Among these are [18F]F-PEB18, 19 (Fig. 1, 1) and the thiazole derivatives [18F]F-MTEB18 (Figure 1, Figure 2, 2) and [18F]SP20320 (Figure 1, Figure 3, 3). Microwave heating was applied for the radiosynthesis of [18F]F-PEB and [18F]F-MTEB but only low radiochemical yields were obtained. The low radiochemical yields were improved later on when thermal heating was employed.21 [18F]F-PEB18, 19 was recently used for the in vivo imaging of mGluR5 in human studies.22 For [18F]SP203 (Figure 1, Figure 3, 3), radiodefluorination was observed in PET studies involving monkeys. In humans, however, low uptake of radioactivity into the skull was observed, suggesting a lower radiodefluorination rate in humans.23 Recently, our group also reported on two novel fluorine-18 labeled analogues of ABP688: [18F]-FPECMO24 (Figure 1, Figure 5, 5) and [18F]-FE-DABP68825 (Figure 1, Figure 6, 6). While [18F]-FPECMO underwent radiodefluorination in vivo in rats, [18F]-FE-DABP688 displayed unfavorable pharmacokinetics. As part of our program to develop fluorine-18 labeled derivatives of ABP688, we designed four novel compounds based on the structural elements of the two most successful mGluR5 PET ligands, [11C]-ABP688 and [18F]SP203. Herein, we report the syntheses and binding affinities of the four novel thiazole containing ABP688 derivatives. Furthermore, we report on the radiolabeling, in vitro and in vivo evaluation of the most promising candidate, [18F]-FTECMO.
Section snippets
Chemistry
The syntheses of four novel mGluR5 ligands (11, 14, 24, and 25) containing thiazole moieties were achieved in satisfactory overall yields, although none of the synthetic steps was optimized. Reference compound 11 was obtained via convergent synthesis (Scheme 1). First, compound 8 was converted into methyl oxime 9 in analogy to the method described for the preparation of intermediate 13. Compound 10 was obtained according to the procedure previously described.20
Discussion
MGluR5 has been shown to be involved in numerous central nervous system disorders. Non-invasive in vivo imaging of the receptor using PET can give further insight into the underlying pathophysiological processes and help understand mGluR5 pharmacology, which in turn will speed up drug development.28, 29 Efforts have been made in recent years to develop suitable mGluR5 PET tracers. However, to date only two mGluR5 PET ligands, [11C]-ABP688 and [18F]SP203, have been fully characterized in humans.
Conclusion
In summary, the syntheses and investigation of four novel thiazole containing ABP688 analogues led to the identification of a high affinity ligand for mGluR5, FTECMO. Its radiolabeled analogue, [18F]-FTECMO, represents a combination of structural elements from [18F]SP203 and [11C]-ABP688, that displayed favorable in vitro characteristics. [18F]-FTECMO is however not suitable for mGluR5 imaging in vivo in rats. The further evaluation of [18F]-FTECMO in higher species such as monkeys and humans
General
Reagents and solvents utilized for experiments were obtained from commercial suppliers (Sigma–Aldrich, Alfa Aesar, Merck and Flucka) and were used without further purification unless stated otherwise. [3H]-M-MPEP was provided by Novartis. Thin layer chromatography performed on pre-coated Silica Gel 60 F245 aluminum sheets suitable for UV absorption detection of compounds was used for monitoring reactions. Nuclear magnetic resonance spectra were recorded with a Bruker 400 MHz spectrometer with an
Acknowledgments
We acknowledge the technical support of Claudia Keller, Petra Wirth and Mathias Nobst. We thank Christophe Lucatelli and Harriet Struthers for fruitful discussion.
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Amino Acids
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