Research article18F-labeled styrylpyridines as PET agents for amyloid plaque imaging
Introduction
Accumulation of excess senile plaques in the brain is strongly associated with the pathogenesis of Alzheimer's disease (AD) [1], [2], [3], [4]. Recent research has focused on the development of potential imaging agents for the direct imaging of β-amyloid (Aβ) aggregates in the living human brain. These imaging agents could be beneficial for the diagnosis and monitoring of therapeutic effects [5], [6], [7], [8], [9], [10].
Several groups, including the authors, have reported series of potential imaging agents for the in vivo imaging of Aβ plaques with positron emission tomography (PET) or single-photon emission computed tomography. Different tracers such as [11C]PIB [9], [11], [12], [13], [11C] 4-N-methylamino-4′-hydroxy-stilbene (SB-13) [14], [15], [18F]FDDNP [16], [17] and [123I]IMPY [18], [19] have been tested clinically and have demonstrated the potential utility of the in vivo imaging of Aβ plaque deposition in the brain. Other structurally similar compounds have been reported [20], [21], [22]. Due to the short half-life of 11C (T1/2=20 min), the supply of 11C agents will likely be limited to facilities with an on-site cyclotron. To broaden the utility of Aβ-plaque-targeting agents, we have then focused our effort on developing 18F-labeled imaging agents (T1/2=110 min). Based on the stilbene backbone structure, we have successfully developed two derivatives: MAPO and PEGN3-stilbene (Fig. 1), which were readily labeled with 18F. To circumvent the problem of high lipophilicity after the addition of a fluoroalkyl group, we have prepared stilbene derivatives with an additional hydroxyl group, such as FMAPO [23] (see Fig. 1). Similarly, we have added polyethylene glycol (PEG) units as tether on the 4-hydroxy group of SB-13 through which the fluorine atom is attached at the end of the PEG chain [fluoropolyethylene glycol (FPEG)] [24]. By varying the chain length of the tethered fluorinated PEG group, we are provided a flexible tool to adjust lipophilicity and to maintain a relatively small size. Both fluorinated tracers FMAPO and FPEGN3-stilbene displayed high binding affinities to Aβ plaques and showed favorable in vivo kinetic properties [23], [24].
In an attempt to further explore 18F-labeled tracers with a different backbone structure, we extended our fluoropegylation approach from stilbene to styrylpyridine series by replacing one of the benzene rings of stilbene with one pyridine ring (Fig. 1). It has been demonstrated that the p-iodo-derivative of styrylpyridine showed more promising in vivo kinetics than the corresponding stilbene derivatives [25]. As an extension of our effort in developing optimal probes, which will require a careful balancing of size and lipophilicity/hydrophilicity while also preserving binding affinity, we have tested various approaches. We have successfully used the strategy of FPEG as the tether attached to the molecule from stilbenes to styrylpyridines. Alternative styrylpyridine derivatives may provide improved in vivo biological properties of targeting Aβ plaques. They may also lead to different profiles of in vivo kinetics and metabolism, which may enhance the signal between target and nontarget regions. Reported herein are the synthesis and biological evaluation of this series of compounds for targeting amyloid plaques.
Section snippets
General
All reagents used in syntheses were commercial products and were used without further purification, unless otherwise indicated. Anhydrous Na2SO4 was used as a drying agent. Microwave reaction was conducted in a Biotage microwave reactor (Biotage Initiator). Preparative thin-layer chromatography (PTLC) was performed with Analtech Uniplate (20×20 cm; 2000 μm). [1H]nuclear magnetic resonance (NMR) and [13C]NMR spectra were obtained with a Bruker spectrometer (Bruker DPX 200). Chemical shifts are
Chemical synthesis
The syntheses of N,N-dimethylamino-substituted styrylpyridine derivative 1 and its fluoropegylated Compound 2 are shown in Scheme 1. Compound 1 was obtained by a Wittig-type (Horner–Wadsworth–Emmons) reaction between diethyl 4-(dimethylamino)benzylphosphonate and 6-chloronicotinaldehyde in the presence of potassium tert-butoxide in DMF (yield: 62%). Direct alkylation of Compound 1 with 2-(2-(2-fluoroethoxy)ethoxy)ethanol with sodium hydride in THF obtained the fluoropegylated Compound 2 (yield:
Conclusion
In conclusion, a new series of novel styrylpyridine derivatives containing an end-capped FPEG (n=3) was successfully prepared as potential PET imaging agents for AD. These styrylpyridine derivatives displayed excellent binding affinities to Aβ plaques. [18F]2 is a potential imaging agent based on its favorable in vivo properties. Both in vitro binding and in vivo biodistribution properties are comparable to [11C]PIB [12], which is currently being used for clinical studies of patients with AD.
Acknowledgments
This work was supported by grants from the National Institutes of Health (AG-022559 to H.F.K. and AG-21868 to M.P.K.). The authors thank Dr. Daniel Skovronsky for his helpful discussion and suggestion.
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