The in vivo binding characteristics of (18)F-GE-180 demonstrate a better signal to noise ratio than (11)C-R-PK11195 due to both a better signal in the lesion and lower nonspecific binding in healthy tissue. These results provide evidence that (18)F-GE-180 is a strong candidate to replace (11)C-R-PK11195.
Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer 18 F-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice. In vivo PET scans revealed an overt age-dependent elevation in whole-brain uptake of 18 F-GE180 in both WT and Tg mice, and a significant increase in whole-brain uptake of 18 F-GE180 (peak-uptake and retention) in old Tg mice compared with young Tg mice and all WT mice. Similarly, the 18 F-GE180 binding potential in hippocampus was highest to lowest in old Tg Ͼ old WT Ͼ young Tg Ͼ young WT mice using MRI coregistration. Ex vivo PET and autoradiography analysis further confirmed our in vivo PET results: enhanced uptake and specific binding (SUV 75% ) of 18 F-GE180 in hippocampus and cortex was highest in old Tg mice followed by old WT, young Tg, and finally young WT mice.18 F-GE180 specificity was confirmed by an in vivo cold tracer competition study. We also examined 18 F-GE180 metabolites in 4-month-old WT mice and found that, although total radioactivity declined over 2 h, of the remaining radioactivity, ϳ90% was due to parent 18 F-GE180. In conclusion, 18 F-GE180 PET scans may be useful for longitudinal monitoring of neuroinflammation during AD progression and treatment.
Neuroinflammation is associated with neurodegenerative disease. PET radioligands targeting the 18-kDa translocator protein (TSPO) have been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with improved signal-to-noise ratio. Flutriciclamide ( 18 F-GE180) is a recently developed thirdgeneration TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for 18 F-GE180 PET in (older) healthy controls. Methods: Ten healthy controls, 6 TSPO high-affinity binders, and 4 mixed-affinity binders were recruited. All subjects underwent detailed neuropsychologic tests, MRI, and a 210-min 18 F-GE180 dynamic PET/CT scan using metabolite-corrected arterial plasma input function. We evaluated 5 different kinetic models: irreversible and reversible 2-tissue-compartment models, a reversible 1-tissue model, and 2 models with an extra irreversible vascular compartment. The minimal scan duration was established using 210-min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis. Results: 18 F-GE180 concentration was higher in plasma than in whole blood during the entire scan duration. The volume of distribution (V T ) was 0.17 in high-affinity binders and 0.12 in mixed-affinity binders using the kinetic model. The model that best represented brain 18 F-GE180 kinetics across regions was the reversible 2-tissue-compartment model (2TCM4k), and 90 min resulted as the optimum scan length required to obtain stable estimates. Logan graphical analysis with arterial input function gave a V T highly consistent with V T in the kinetic model, which could be used for voxelwise analysis. Conclusion: We report for the first time, to our knowledge, the kinetic properties of the novel third-generation TSPO PET ligand 18 F-GE180 in humans: 2TCM4k is the optimal method to quantify the brain uptake, 90 min is the optimal scan length, and the Logan approach could be used to generate parametric maps. Although these control subjects have shown relatively low V T , the methodology presented here forms the basis for quantification for future PET studies using 18 F-GE180 in different pathologies.
PurposePET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [11C]PK-11195 limits accurate quantification. [18F]GE-180, a novel TSPO ligand, displays superior binding to [11C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [18F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures.MethodsTen volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [18F]GE-180. Kinetic modelling of time–activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution (VT) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region.ResultsThe two-tissue compartment model was the best model. The average regional delivery rate constant (K1) was 0.01 mL cm−3 min−1 indicating low extraction across the blood–brain barrier (1 %). The estimated median VT across all ROIs was also low, ranging from 0.16 mL cm−3 in the striatum to 0.38 mL cm−3 in the thalamus. There were no significant differences in VT between HABs and MABs across all ROIs.ConclusionA reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low VT estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [18F]GE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3444-z) contains supplementary material, which is available to authorized users.
and 6 GE Healthcare plc, Amersham, United Kingdom N-methyl D-aspartate (NMDA) ion channels play a key role in a wide range of physiologic (e.g., memory and learning tasks) and pathologic processes (e.g., excitotoxicity). To date, suitable PET markers of NMDA ion channel activity have not been available. 18 F-GE-179 is a novel radioligand that selectively binds to the open/active state of the NMDA receptor ion channel, displacing the binding of 3 H-tenocyclidine from the intrachannel binding site with an affinity of 2.4 nM. No significant binding was observed with 10 nM GE-179 at 60 other neuroreceptors, channels, or transporters. We describe the kinetic behavior of the radioligand in vivo in humans. Methods: Nine healthy participants (6 men, 3 women; median age, 37 y) each underwent a 90-min PET scan after an intravenous injection of 18 F-GE-179. Continuous arterial blood sampling over the first 15 min was followed by discrete blood sampling over the duration of the scan. Brain radioactivity (KBq/mL) was measured in summation images created from the attenuation-and motion-corrected dynamic images. Metabolite-corrected parent plasma input functions were generated. We assessed the abilities of 1-, 2-, and 3-compartment models to kinetically describe cerebral time-activity curves using 6 bilateral regions of interest. Parametric volume-of-distribution (V T ) images were generated by voxelwise rank-shaping regularization of exponential spectral analysis (RS-ESA). Results: A 2-brain-compartment, 4-rate-constant model best described the radioligand's kinetics in normal gray matter of subjects at rest. At 30 min after injection, 37% of plasma radioactivity represented unmetabolized 18 F-GE-179. The highest mean levels of gray matter radioactivity were seen in the putamina and peaked at 7.5 min. A significant positive correlation was observed between K 1 and V T (Spearman ρ 5 0.398; P 5 0.003). Between-subject coefficients of variation of V T ranged between 12% and 16%. Voxelwise RS-ESA yielded similar V T s and coefficients of variation. Conclusion: 18 F-GE-179 exhibits high and rapid brain extraction, with a relatively homogeneous distribution in gray matter and acceptable between-subject variability. Despite its rapid peripheral metabolism, quantification of 18 F-GE-179 V T is feasible both within regions of interest and at the voxel level. The specificity of 18 F-GE-179 binding, however, requires further characterization with in vivo studies using activation and disease models.
Space travel will expose people to high-energy, heavy particle radiation, and the cognitive deficits induced by this exposure are not well understood. To investigate the short-term effects of space radiation, we irradiated 4-month-old Alzheimer’s disease (AD)-like transgenic (Tg) mice and wildtype (WT) littermates with a single, whole-body dose of 10 or 50 cGy 56 Fe ions (1 GeV/u) at Brookhaven National Laboratory. At ~1.5 months post irradiation, behavioural testing showed sex-, genotype-, and dose-dependent changes in locomotor activity, contextual fear conditioning, grip strength, and motor learning, mainly in Tg but not WT mice. There was little change in general health, depression, or anxiety. Two months post irradiation, microPET imaging of the stable binding of a translocator protein ligand suggested no radiation-specific change in neuroinflammation, although initial uptake was reduced in female mice independently of cerebral blood flow. Biochemical and immunohistochemical analyses revealed that radiation reduced cerebral amyloid-β levels and microglia activation in female Tg mice, modestly increased microhemorrhages in 50 cGy irradiated male WT mice, and did not affect synaptic marker levels compared to sham controls. Taken together, we show specific short-term changes in neuropathology and behaviour induced by 56 Fe irradiation, possibly having implications for long-term space travel.
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