Synthesis and evaluation of 11C-labeled naphthalene derivative as a novel non-peptidergic probe for the β-secretase (BACE1) imaging in Alzheimer's disease brain.

As a first trial for in vivo imaging of β-secretase (BACE1) in Alzheimer's disease brain, we applied a novel non-peptidergic small molecule which has high affinity to the enzyme, naphthalene-1-carboxylic acid (3'-chloro-4'-fluoro-4-piperazin-1-yl-biphenyl-3-yl)amide (NCFB) into positron emission tomography (PET) probe. In the current study, N-(11)C-methylated compound of NCFB, [(11)C]Me-NCFB was synthesized and evaluated for the visualization of BACE1 in brain. BACE1 inhibitory constant was measured by FRET assay. [(11)C]Me-NCFB was synthesized from NCFB with [(11)C]methyl triflate. To evaluate properties of [(11)C]Me-NCFB, log P value, stability in mouse plasma and brain uptake index were measured. The biodistribution in 6-week-old ddY mice was also studied. BACE1 inhibitory constant showed an affinity of Me-NCFB to the enzyme (IC50=2.3 ± 0.80 μM). [(11)C]Me-NCFB was synthesized in a 3.0% ± 0.55% decay-corrected radiochemical yield. [(11)C]Me-NCFB showed high lipophilicity, high stability in mouse plasma and blood-brain barrier (BBB) permeability. Injected to 6-week-old ddY mice, [(11)C]Me-NCFB penetrated BBB and was retained in the brain (0.79% ± 0.22% ID/g at 2 min and 0.75% ± 0.08% ID/g at 60 min after injection, respectively), moreover, rapid blood clearance was observed. [(11)C]Me-NCFB could have a potential as a PET probe for the imaging of BACE1 in the brain.