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ItemDevelopment of a candidate for PET imaging of BACE1 in Alzheimer's diseaseDOWN, RUSSELL ( 2015)Alzheimer's disease (AD) is the most common form of dementia but there is currently no cure or disease modifying treatment. The pathological processes which lead to AD begin up to 20 years before the onset of symptoms, offering a large window for diagnosis and potential therapeutic intervention. β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is an aspartyl protease involved in the pathogenesis of AD. BACE1 levels are increased in AD patients and this elevation is known to occur early in the course of the disease; however, there is currently no method for measuring cortical BACE1 levels in vivo. It is hypothesised that the development of a BACE1 positron emission tomography (PET) imaging agent could have clinical utility for AD diagnosis as well as offering other benefits to AD research. A series of analogues of the hit compound (E)-2-(5-(3,4-dimethoxyphenyl)thiazol-2-yl)-3-(4-hydroxy-3-methoxyphenyl)acrylonitrile, identified from a screen of 70 compounds against BACE1 activity, was synthesised in order to generate a structure activity relationship. Initial attempts to radiolabel the general scaffold of the compounds with the 18F isotope by direct labelling were unsuccessful due to the instability of the scaffold under radiofluorination conditions; however, a route to radiolabel the scaffold was achieved by utilising [18F]-fluorobenzaldehyde as a prosthetic labelling group. The ability of the compounds to bind to BACE1 was assessed by a surface plasmon resonance (SPR) inhibition in solution assay. While a small number of compounds displayed limited activity, IC50 values could not be generated and most compounds were inactive. In addition, most of the compounds were too insoluble to be assessed for membrane permeability using the parallel artificial membrane permeability assay (PAMPA), although a small number of more soluble compounds were shown to have high permeability. Due to the slow progress and problems encountered in developing a de novo BACE1 PET imaging candidate, it was decided to modify an existing BACE1 inhibitor to incorporate the 18F radiolabel. MK-8931 (Merck) has a high affinity for BACE1 and is the most advanced clinical candidate for BACE1 inhibition and a synthetic route was developed to introduce a fluorine atom to the molecule. Following the synthesis of MK-8931, achieved by modification of a literature procedure, a radiofluorinated analogue, (S)-2-amino-6-(4-(5-(3-[18F]-fluoroprop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-one, was prepared; unfortunately, the amount of labelled material was low and purification was not attempted. Analysis of (S)-2-amino-6-(4-(5-(3-fluoroprop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-one by SPR showed an IC50 of 2.05 nM compared to 5.87 nM for that of MK-8931, and the passive membrane permeability of both compounds as measured by PAMPA was very similar. These results suggest that should the radiosynthesis be optimised, (S)-2-amino-6-(4-(5-(3-[18F]-fluoroprop-1-yn-1-yl)pyridin-3-yl)thiophen-2-yl)-3,6-dimethyl-5,6-dihydropyrimidin-4(3H)-one would be a good candidate for PET imaging of BACE1.