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Several novel norcamphor derivatives were designed and synthesized as uncompetitive NMDA receptor antagonists at the phencyclidine (PCP) binding site. Such compounds have potential as ligands for understanding and possibly the treatment of several neurodegenerative disorders and other glutamate-dependent disorders. We examined the toxic effects of the compounds as compared with memantine, an NMDA receptor antagonist that is FDA approved for treatment of Alzheimer’s disease, by testing these compounds on two cell lines: MDCK (to mimic blood brain barrier) and N2a (a neuronal cell line). The compounds showed toxicity profiles similar to those of memantine i.e., dose dependence above 100 μM and IC50 values above 150 μM for each cell line. It is known that the serum level of memantine under therapeutic conditions in patients is about 1 µM, indicting these compounds could have acceptable therapeutic indexes. 2-Phenyl-N-(2-(piperidin-1-yl) ethyl)bicyclo[2.2.1]heptan-2-amine (5a) was found to possess acceptable toxicity profiles in both cell lines. Interestingly, this was the compound identified as a good lead in our previous studies based on binding and anticonvulsant (MES) activity studies. It has thus emerged as an excellent lead compound for further studies.

The use of fluorinated molecules as drugs and imaging agents for CNS disorders has been studied extensively over the years. Incorporating a fluorine atom into the structure of a drug changes its physiochemical properties and can thereby lead to much more desirable pharmacokinetic and pharmacodynamic properties. This change can help to facilitate blood-brain barrier permeability, which is a critical matter for drugs intended for CNS activities. Fluorine incorporation into structures of drugs for the treatment of neurodegenerative diseases has been an attractive field for drug discovery. Such incorporation can greatly influence the physicochemical properties, metabolic stability and receptor binding affinity of the resulting molecule. Some studies have shown that when a proton was substituted with fluorine, the binding or inhibitory potency was greatly increased. The fluorine-18 isotope, (18)F, is utilized in detection and diagnosis of neurodegenerative diseases, whereas (19)F compounds are used in the treatment of these diseases and in MRI. (18)F is widely used in PET imaging because it offers the advantage of a longer half-life compared with other radionuclides. It is used for imaging various receptors and transporters that have been linked to neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and multiple system atrophy. Fluorine plays an important role in the diagnosis and treatment of many CNS diseases, including neurodegenerative disorders. The use of fluorine in the diagnosis and treatment of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, will be discussed in this review.

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