Follow-up of b-amyloid (Ab) deposition in transgenic mouse models of Alzheimer disease (AD) would be a valuable translational tool in the preclinical evaluation of potential antiamyloid therapies. This study aimed to evaluate the ability of the clinically used PET tracer 11 C-Pittsburgh compound B ( 11 C-PIB) to detect changes over time in Ab deposition in the brains of living mice representing the APP23, Tg2576, and APP swe -PS1 dE9 transgenic mouse models of AD. Methods: Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 729, 12, 15, and 18222 mo of age. Regional 11 C-PIB retention was quantitated as distribution volume ratios using Logan graphical analysis with cerebellar reference input, as radioactivity uptake ratios between the frontal cortex (FC) and the cerebellum (CB) during the 60-min scan, and as bound-tofree ratios in the late washout phase (40260 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate 11 C-PIB binding to Ab deposits. Additionally, the presence of Ab deposits was evaluated in vitro using staining with thioflavin-S and Ab 1-40 , Ab 1-16 , and Ab N3(pE) immunohistochemistry. Results: Neocortical 11 C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S-positive Ab deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n 5 2), increasing to 1.38 6 0.03 (n 5 3) and 1.34 (n 5 1) at 18 and 21 mo of age, respectively. An increase was also observed in bound-to-free ratios for the FC between young (7-to 12-mo-old) and old (15-to 22-mo-old) APP23 mice. Binding of 11 C-PIB to Ab-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in 11 C-PIB retention were observed in aging Tg2576 or APP swe -PS1 dE9 mice in vivo, although in the latter, extensive Ab deposition was already observed at 9 mo of age with immunohistochemistry. Conclusion: The results suggest that 11 C-PIB binding to Ab deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Ab plaques. Longitudinal in vivo 11 C-PIB uptake studies are possible in APP23 mice.

Preclinical animal model studies of brain energy metabolism and neuroinflammation in Alzheimer's disease have produced conflicting results, hampering both the elucidation of the underlying disease mechanism and the development of effective Alzheimer's disease therapies. Here, we aimed to quantify the relationship between brain energy metabolism and neuroinflammation in the APP/PS1-21 transgenic mouse model of Alzheimer's disease using longitudinal in vivoF-FDG and F-DPA-714) PET imaging and ex vivo brain autoradiography. APP/PS1-21 (TG, n = 9) and wild type control mice (WT, n = 9) were studied longitudinally every third month from age 6 to 15 months withF-FDG and F-DPA-714 with a one-week interval between the scans. Additional TG (n = 52) and WT (n = 29) mice were used for ex vivo studies. In vivo, theF-FDG SUVs were lower and the F-DPA-714 binding ratios relative to the cerebellum were higher in the TG mouse cortex and hippocampus than in WT mice at age 12 to 15 months ( p< 0.05). The ex vivo cerebellum binding ratios supported the results of the in vivoF-DPA-714 studies but not the F-FDG studies. This longitudinal PET study demonstrated decreased energy metabolism and increased inflammation in the brains of APP/PS1-21 mice compared to WT mice.

Based on its pharmacokinetic profile, [(18)F]flutemetamol showed potential as a PET tracer for preclinical imaging. It showed good brain uptake and was bound to Aβ deposits in the brain of Tg2576 mice. However, its high lipophilicity might complicate the analysis of PET data, particularly in small-animal imaging.

BackgroundRecently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer’s disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice.FindingsTransgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [18 F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment.ConclusionsJZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing APP and PSEN1 mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease. Methods: TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [ 18 F]DPA-714 (TSPO, neuroinflammation), [ 18 F]Florbetaben (Aβ) and [ 18 F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[ 18 F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aβ, NeuN, NeuroChrom) and Tau (S)-[ 18 F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. Results: [ 18 F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. In vivo [ 18 F]ASEM PET revealed an age-dependent increase uptake in the striatum and pallidum/nucleus basalis of Meynert in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. In vivo [ 18 F]Florbetaben PET scanning detected Aβ accumulation at 18 m, and (S)-[ 18 F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aβ plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aβ plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the Aβ plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both ge...

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PurposeMany neurological conditions result in the overexpression of the translocator protein 18 kDa (TSPO), today recognized as a biomarker for microglial activation and neuroinflammation imaging. The pyrazolo[1,5-a]pyrimidine acetamides are a particularly attractive class of TSPO-specific ligands, prompting the development of several positron emission tomography (PET) radiotracers. This includes F-DPA, a recently reported fluorinated ligand (K i = 1.7 nM), wherein the fluorine atom is directly linked to the phenyl moiety without the presence of an alkyl or alkoxy spacer chain. Reported here is the preparation of [18F]F-DPA using [18F]Selectfluor bis(triflate) and the preliminary evaluation of [18F]F-DPA in healthy rats. Its metabolic profile and biodistribution in rats are compared with that of [18F]DPA-714, a closely related structure.Procedures[18F]F-DPA was synthesized by electrophilic fluorination using [18F]Selectfluor bis(triflate), [18F]DPA-714 was synthesized by conventional nucleophilic fluorination. The biodistribution of both radiotracers was compared in Sprague Dawley rats. Radiometabolites of both radiotracers in plasma and brain homogenates were analyzed by radioTLC.ResultsThe radiochemical yield of [18F]F-DPA was 15 ± 3 % and the specific activity was 7.8 ± 0.4 GBq/μmol. The radiochemical purity exceeded 99 %. The in vivo time activity curves of [18F]F-DPA demonstrate rapid entry into the brain and a concentration equilibrium at 20–30 min after injection. The metabolic profiles at 90 min after radiotracer injection in the plasma show that unchanged [18F]F-DPA and [18F]DPA-714 account for 28.3 ± 6.4 and 11.1 ± 2.6 % of the remaining radioactivity, respectively. In the brain, unchanged [18F]F-DPA accounts for 93.5 ± 2.8 % of the radioactivity; whereas for [18F]DPA-714, this value is 53.6 ± 1.6 %.Conclusions[18F]Selectfluor bis(triflate) was successfully used to label F-DPA with fluorine-18. The labeling position on the aromatic moiety imparts a higher stability compared to [18F]DPA-714 with regard to in vivo metabolism. [18F]F-DPA is a promising new radiotracer and warrants further investigation in animal models of disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-1040-z) contains supplementary material, which is available to authorized users.