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  • As a continuation of our search for a selective


    As a continuation of our search for a selective AChE radioligand bearing a meta-F substituted N-benzyl moiety, we designed and synthesized a novel meta-F-CP-118,954 analog along with a meta-18F-labeled form via diaryliodonium salt-based precursor (Fig. 1). For comparative purposes, we incorporate the aromatic fluorine in all three positions of the phenyl ring. A meta-18F-labeled CP-118,954 analog and the already reported ortho- and para-18F-labeled CP-118,954 analogs were prepared (Scheme 1) and evaluated for both in vitro and in vivo activities related to the AChE expression.
    Materials and methods
    Results and discussion
    Conclusion This study provides in vivo neuropharmacological evidence that the distribution into the rat 84 regions of fluorinated ligands with affinity toward AChE in the low nanomolar range critically depends upon the position of aromatic fluorine. Indeed, among the three fluorinated positional isomers of the known AChE inhibitor (CP-118,954, 1), the meta-F isomer (3), with in vitro AChE inhibition potency close to that of the parent compound 1 (IC50's 1.4 and 1.2nM for 3 and 1, respectively), exhibited the best in vivo neuropharmacological properties, in terms of selective delivery and disposition into the rat brain regions. Herein, it has been demonstrated that 3, intraperitoneally administered, permeates the brain, most likely by passive diffusion (log D at pH7.4 equals 2.48), is metabolically stable in rat brain and causes, better than the ortho-F (2) and para-F (4), produces a significant release of ACh in striatum (an AChE-rich region) with a significantly detectable effect at 3h post-treatment. As a major outcome of this study, a radiolabeled ligand ([18F]3) for PET imaging studies was synthesized and compared with the other two 18F-containing positional isomers of CP-118,954 ([18F]2 and [18F]4). In the comparative PET imaging study, [18F]3 showed higher radioactivity in striatum of normal rat brain, which visually reflected its higher in vitro AChE-binding affinity, but also a target (striatum) to non-target (cerebellum) uptake ratio, as assessed by SUVR, significantly higher than that of [18F]2 (p<0.005) and [18F]4 (p<0.001). In addition, blocking studies showed that the [18F]3 uptake in rat brain striatum is altered by the AChE inhibitor rivastigmine, and much less by haloperidol. In the absence of a comparative blood sampling, it cannot be ruled out that the different effects of the three 18F positional isomers are due to variations in metabolism, besides the observed differences in AChE affinity as assessed by the in vitro IC50 values. Taken together, these findings demonstrated that [18F]3 binds selectively to AChE-rich regions into the rat brain, supporting its suitability as AChE-targeted PET imaging ligand for the assessment of cholinergic activity into the brain and providing useful insights into the position-dependent AChE fluorinated ligands' disposition.
    Acknowledgments and disclosures The authors are grateful to professor Yearn Seong Choe (Sungkyunkwan University School of Medicine) and professor Byoung Wook Choi (Hanbat National University) for help in AChE inhibition assay. This study was supported by a grant of the Korean Health Technology R&D Project through the Korean Health Industry Development Instituted (KHIDI), funded by the Ministry of Health & Welfare, Republic Korea (No. HI12C-0035-030015). The authors declare that they have no conflict of interest.
    Introduction Cadmium is a persistent environmental neurotoxic pollutant (ATSDR, 2012). Exposure to this metal has been associated with numerous human pathologies as osteoporosis, kidney dysfunction, respiratory ailments, birth defects and neurodegenerative diseases (Jahan et al., 2014; Mendez-Armenta and Rios, 2007). Cadmium induces cognitive disorders similar to Alzheimer’s disease (AD) symptoms (Wang and Du, 2013), signaling it as a possible etiological factor of AD (Jiang et al., 2007). However, the mechanisms through which cadmium induces cognitive dysfunctions remain unknown.