Herein we aimed to evaluate the utility of N-(2,5-dimethoxybenzyl)-2-18F-fluoro-N-(2-phenoxyphenyl)acetamide (18F-PBR06) for detecting alterations in translocator protein (TSPO) (18 kDa), a biomarker of microglial activation, in a mouse model of Alzheimer's disease (AD). Methods Wild-type (wt) and AD mice (i.e., APPL/S) underwent 18F-PBR06 PET imaging at predetermined time points between the ages of 5–6 and 15–16 mo. MR images were fused with PET/CT data to quantify 18F-PBR06 uptake in the hippocampus and cortex. Ex vivo autoradiography and TSPO/CD68 immunostaining were also performed using brain tissue from these mice. Results PET images showed significantly higher accumulation of 18F-PBR06 in the cortex and hippocampus of 15- to 16-mo-old APPL/S mice than age-matched wts (cortex/muscle: 2.43 ± 0.19 vs. 1.55 ± 0.15, P < 0.005; hippocampus/muscle: 2.41 ± 0.13 vs. 1.55 ± 0.12, P < 0.005). And although no significant difference was found between wt and APPL/S mice aged 9–10 mo or less using PET (P = 0.64), we were able to visualize and quantify a significant difference in 18F-PBR06 uptake in these mice using autoradiography (cortex/striatum: 1.13 ± 0.04 vs. 0.96 ± 0.01, P < 0.05; hippocampus/striatum: 1.266 ± 0.003 vs. 1.096 ± 0.017, P < 0.001). PET results for 15- to 16-mo-old mice correlated well with autoradiography and immunostaining (i.e., increased 18F-PBR06 uptake in brain regions containing elevated CD68 and TSPO staining in APPL/S mice, compared with wts). Conclusion 18F-PBR06 shows great potential as a tool for visualizing TSPO/microglia in the progression and treatment of AD.
Cancer cells reprogram their metabolism to meet increased biosynthetic demands, commensurate with elevated rates of replication. Pyruvate kinase M2 (PKM2) catalyzes the final and rate-limiting step in tumor glycolysis, controlling the balance between energy production and the synthesis of 2
Most physiologic effects of the renin angiotensin system (RAS) are mediated via the angiotensin (Ang) type 1 receptor (AT 1 R). The 18 FFPyKYNE derivative of the clinically used AT 1 R blocker losartan exhibits high binding selectivity for kidney AT 1 R and rapid metabolism in rats. The aim of this study was to further assess the binding profile of this novel PET agent for imaging AT 1 R in rats and pigs. Methods: In vitro binding assays were performed with 18 F-FPyKYNElosartan in rat kidneys. Male Sprague-Dawley rats were used to assess dosimetry, antagonistic efficacy via blood pressure measurements, and presence of labeled metabolites in kidneys. Testretest PET imaging, blocking with AT 1 R antagonist candesartan (10 mg/kg), and plasma metabolism analysis were performed in female Yorkshire pigs. Results: 18 F-FPyKYNE-losartan bound with high affinity (dissociation constant of 49.4 ± 18.0 nM and maximal binding of 348 ± 112 fmol/mm 2 ) to rat kidney AT 1 R. It bound strongly to plasma proteins in rats (97%), and its labeled metabolites displayed minimal interference on renal AT 1 R binding. FPyKYNE-losartan fully antagonized the Ang II pressor effect, albeit with 4-fold potency reduction (the effective dose inhibiting 50% of the Ang II-induced maximal pressor response of 25.5 mg/kg) relative to losartan. PET imaging exhibited high kidney-to-blood contrast and slow renal clearance, with an SUV of 14.1 ± 6.2. Excellent reproducibility was observed in the calculated test-retest variability (7.2% ± 0.75%). Only hydrophilic-labeled metabolites were present in plasma samples, and renal retention was reduced (−60%) at 10-15 min after blockade with candesartan. Conclusion: 18 F-FPyKYNE-losartan has a favorable binding profile and displays high potential for translational work in humans as an AT 1 R PET imaging agent.
BackgroundThis study aims to further evaluate the specificity and selectivity of [18F]FTC-146 and obtain additional data to support its clinical translation.MethodsThe binding of [19F]FTC-146 to vesicular acetylcholine transporter (VAChT) was evaluated using [3H]vesamicol and PC12A123.7 cells in an in vitro binding assay. The uptake and kinetics of [18F]FTC-146 in S1R-knockout mice (S1R-KO) compared to wild-type (WT) littermates was assessed using dynamic positron emission tomography (PET) imaging. Ex vivo autoradiography and histology were conducted using a separate cohort of S1R-KO/WT mice, and radiation dosimetry was calculated from WT mouse data (extrapolated for human dosing). Toxicity studies in Sprague–Dawley rats were performed with a dose equivalent to 250× the anticipated clinical dose of [19F]FTC-146 mass.Results and discussionVAChT binding assay results verified that [19F]FTC-146 displays negligible affinity for VAChT (Ki = 450 ± 80 nM) compared to S1R. PET images demonstrated significantly higher tracer uptake in WT vs. S1R-KO brain (4.57 ± 1.07 vs. 1.34 ± 0.4 %ID/g at 20–25 min, n = 4, p < 0.05). In S1R-KO mice, it was shown that rapid brain uptake and clearance 10 min post-injection, which are consistent with previous S1R-blocking studies in mice. Three- to fourfold higher tracer uptake was observed in WT relative to S1R-KO mouse brains by ex vivo autoradiography. S1R staining coincided well with the autoradiographic data in all examined brain regions (r2 = 0.85–0.95). Biodistribution results further demonstrated high [18F]FTC-146 accumulation in WT relative to KO mouse brain and provided quantitative information concerning tracer uptake in S1R-rich organs (e.g., heart, lung, pancreas) for WT mice vs. age-matched S1R-KO mice. The maximum allowed dose per scan in humans as extrapolated from mouse dosimetry was 33.19 mCi (1228.03 MBq). No significant toxicity was observed even at a 250X dose of the maximum carrier mass [19F]FTC-146 expected to be injected for human studies.ConclusionsTogether, these data indicate that [18F]FTC-146 binds specifically to S1Rs and is a highly promising radiotracer ready for clinical translation to investigate S1R-related diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0122-2) contains supplementary material, which is available to authorized users.
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