Alzheimer's disease, the most common age-related neurodegenerative disorder, is characterized by the invariant cerebral accumulation of ß-amyloid peptide. In humans, [18F]-AV-45-PET is currently studied to follow-up in vivo amyloid accumulation. Here, [18F]-AV-45 was used to visualize and follow-up amyloid deposition in a transgenic mouse model of amyloidosis (APP/PS1-21), ex vivo by autoradiography and in vivo by microPET. [18F]-AV-45 was produced in a fully automated procedure suitable for routine clinical application. Ex vivo autoradiography was conducted in 3, 8 and 12 month-old APP/PS1-21 and age-matched C57Bl6 mice as controls. Under anesthesia, the mice were injected with [18F]-AV-45 and euthanatized 30 min after injection. Frozen brain tissue was then coronally cut into 20 μm-thick sections, exposed to imaging plate and scanned with a phosphor-imager. The intensity of radioactive signals was measured in cortex, hippocampus, striatum and cerebellum (control region). Longitudinal PET studies were performed at 3, 5, 8 and 12 months in APP/PS1-21 and C57Bl6 mice. PET images were recorded on a high-resolution small-animal PET imaging device and co-registered with T2-weighted magnetic resonance images (MRI) to ensure proper ROI placement (region of interest). Thioflavin-S staining was performed on APP/PS1-21 and C57Bl6 brain sections. Autoradiograms of the brain sections highlighted an increase of [18F]-AV-45 uptake in APP/PS1 mice compared to age-matched controls (3 months: +23%, 8 months: +53%, 12 months: +29%). At 8 months, an intense labeling (compared to age-matched control animals) was observed in the cortical regions (+ 72%), hippocampus (+ 47%) and striatum (+ 42%). This intense accumulation of radiotracer was found in close association with thioflavin S-positive-amyloid plaques. PET study confirmed the increased [18F]-AV-45 uptake in APP/PS1 mice compared to control animals and demonstrated that tracer uptake increased in tight association with age and amyloid plaques revealed by thioflavin S. This longitudinal assessment demonstrated the ability of [18F]-AV-45-microPET to visualize and quantitatively measure progressive amyloid accumulation in living APP/PS1 mice.
We report here the syntheses of N-substituted quinolinimide derivatives displaying sufficient affinity and high selectivity for δ-opioid receptors. Among 9-subsituted derivatives, one showed much higher selectivity for the δ receptor in binding assays than the δ antagonist methylnaltrindole (6: Ki = 42 nM; μ/δ and κ/δ > 238 on rat brain membranes) and antagonist properties. This compound was labeled with carbon-11 (t1/2 = 20.4 min) as a potential radioligand for the noninvasive assessment of δ opioid receptors in vivo with positron emission tomography (PET). A high yielding radiosynthesis of [11C]-6, based on the [11C]methyl introduction on the pyridine moiety by a Stille reaction, was described (radiochemical yield = 60 ± 10%, specific activities = 0.8 to 1.5 Ci/μmol). The in vivo pharmacological profile in rats indicated that the radiotracer crossed the blood−brain barrier but was not stable and underwent rapid degradation in both plasma and brain. No specific binding was consequently revealed.
