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Background: P2X7 receptor has emerged as a potentially superior PET imaging marker to TSPO, the gold standard for imaging glial reactivity. [ 11 C]SMW139 is the most recently developed radiotracer to image P2X7 receptor. The aim of this study was to image reactive glia in the APP/PS1-21 transgenic (TG) mouse model of Aβ deposition longitudinally using [ 11 C]SMW139 targeting P2X7 receptor and to compare tracer uptake to that of [ 18 F]F-DPA targeting TSPO at the final imaging time point. TG and wild type (WT) mice underwent longitudinal in vivo PET imaging using [ 11 C]SMW139 at 5, 8, 11, and 14 months, followed by [ 18 F]F-DPA PET scan only at 14 months. In vivo imaging results were verified by ex vivo brain autoradiography, immunohistochemical staining, and analysis of [ 11 C]SMW139 unmetabolized fraction in TG and WT mice., Results: Longitudinal change in [ 11 C]SMW139 standardized uptake values (SUVs) showed no statistically significant increase in the neocortex and hippocampus of TG or WT mice, which was consistent with findings from ex vivo brain autoradiography. Significantly higher [ 18 F]F-DPA SUVs were observed in brain regions of TG compared to WT mice. Quantified P2X7-positive staining in the cortex and thalamus of TG mice showed a minor increase in receptor expression with ageing, while TSPO-positive staining in the same regions showed a more robust increase in expression in TG mice as they aged. [ 11 C]SMW139 was rapidly metabolized in mice, with 33% of unmetabolized fraction in plasma and 29% in brain homogenates 30 min after injection., Conclusions: [ 11 C]SMW139, which has a lower affinity for the rodent P2X7 receptor than the human version of the receptor, was unable to image the low expression of P2X7 receptor in the APP/PS1-21 mouse model. Additionally, the rapid metabolism of [ 11 C]SMW139 in mice and the presence of several brain-penetrating radiometabolites significantly impacted the analysis of in vivo PET signal of the tracer. Finally, [ 18 F]F-DPA targeting TSPO was more suitable for imaging reactive glia and neuroinflammatory processes in the APP/PS1-21 mouse model, based on the findings presented in this study and previous studies with this mouse model., (© 2024. The Author(s).)

Background: In the development of new 18 F-labelled tracers, it is important to assess the amount of released [ 18 F]fluoride taken up in the bones of experimental animals because all 18 F-labelled PET-tracers are prone, to lesser or higher degree, to undergo defluorination, with subsequent release of [ 18 F]fluoride during scanning. However, the pharmacokinetics of [ 18 F]fluoride in bones and other organs of healthy rats have not been well documented in a comprehensive manner. We aimed to study pharmacokinetics of [ 18 F]NaF in rats in order to increase our understanding of the biodistribution of [ 18 F]fluoride originating from defluorination of 18 F-labelled tracers. We studied [ 18 F]fluoride uptake in Sprague Dawley rat bones, including the epiphyseal parts of the tibia and radius, the mandible, ilium, lumbar vertebrae, costochondral joints, tibia, radius, and ribs, with 60-min in vivo PET/CT imaging. Kinetic parameters, K 1 , K i , K i /K 1 , and k 3 were calculated with a three-compartment model. In addition, separate groups of male and female rats were studied with ex vivo bone and soft tissue harvesting and gamma counting over a 6-h period., Results: [ 18 F]fluoride perfusion and uptake varied among the different bones. [ 18 F]fluoride uptake was higher in trabecular bones, due to high perfusion and osteoblastic activity, compared to cortical bones. In soft tissues, the organ-to-blood uptake ratios increased over time in the eyes, lungs, brain, testes, and ovaries during the 6 h study period., Conclusion: Understanding the pharmacokinetics of [ 18 F]fluoride in various bones and soft tissues is highly useful for assessing 18 F-labelled radiotracers that release [ 18 F]fluoride., (© 2023. The Author(s).)

Background: Availability of the α 2C -adrenoceptor (α 2C -AR) positron emission tomography (PET) tracer, [ 11 C]ORM-13070, and the α 2C -AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders. This translational study employed [ 11 C]ORM-13070 autoradiography and PET to determine α 2C -AR occupancy by ORM-12741 in rat and human brain, respectively., Results: ORM-12741 has high affinity (K i : 0.08 nM) and potent antagonist activity (K b : 0.04 nM) as well as selectivity (K i estimates for the human α 2A -AR and α 2B -AR were 8.3 nM and 0.8 nM, respectively) for the human α 2C -AR subtype. [ 11 C]ORM-13070 had highest uptake in the basal ganglia of rat and human brain. Pretreatment with ORM-12741 inhibited [ 11 C]ORM-13070 binding in rat striatum in a time- and dose-dependent manner at 10 and 50 µg/kg (s.c.) with an EC 50 estimate of 1.42 ng/mL in rat plasma, corresponding to protein-free drug concentration of 0.23 nM. In the living human brain, time- and dose-related α 2C -AR occupancy was detected with EC 50 estimates of 24 ng/mL and 31 ng/mL for the caudate nucleus and putamen, respectively, corresponding to protein-free concentrations in plasma of 0.07 nM and 0.1 nM. Modelling-based maximum α 2C -AR occupancy estimates were 63% and 52% in the caudate nucleus and the putamen, respectively., Conclusions: ORM-12741 is a selective α 2C -AR antagonist which penetrates the rat and human brain to occupy α 2C -ARs in a manner consistent with its receptor pharmacology. Trial registration number and date of registration: ClinicalTrial.cov NCT00829907. Registered 11 December 2008. https://clinicaltrials.gov/ .

Background: Several radiometal-labeled, exendin-based tracers that target glucagon-like peptide-1 receptors (GLP-1R) have been intensively explored for β cell imaging. The main obstacle has been the high uptake of tracer in the kidneys. This study aimed to develop a novel GLP1-R-specific tracer, with fluorine-18 attached to exendin-4, to label β cells for clinical imaging with PET (positron emission tomography). We hypothesized that this tracer would undergo reduced kidney uptake. 18 F-labeled [Nle 14 ,Lys 40 ]exendin-4 analog ([ 18 F]exendin-4) was produced via Cu-catalyzed click chemistry. The biodistribution of [ 18 F]exendin-4 was assessed with ex vivo organ γ-counting and in vivo PET imaging. We also tested the in vivo stability of the radiotracer. The localization of 18 F radioactivity in rat and human pancreatic tissue sections was investigated with autoradiography. Receptor specificity was assessed with unlabeled exendin-3. Islet labeling was confirmed with immunohistochemistry. The doses of radiation in humans were estimated based on biodistribution results in rats., Results: [ 18 F]exendin-4 was synthesized with high yield and high specific activity. Results showed specific, sustained [ 18 F]exendin-4 uptake in pancreatic islets. In contrast to previous studies that tested radiometal-labeled exendin-based tracers, we observed rapid renal clearance of [ 18 F]exendin-4., Conclusions: [ 18 F]exendin-4 showed promise as a tracer for clinical imaging of pancreatic β cells, due to its high specific uptake in native β cells and its concomitant low kidney radioactivity uptake.

Background: Tumor hypoxia is linked to invasion and metastasis but whether this associates with tumor growth rate is not well understood. We aimed to study the relationship between hypoxia evaluated with the positron emission tomography (PET) tracer [(18)F]EF5 and tumor growth. Our second goal was to assess the variability in the uptake of [(18)F]EF5 in tumor between two scans., Methods: Four human head and neck squamous cell carcinoma (UT-SCC) cell lines were xenografted in flank or neck of nude mice, and tumor size was closely monitored over the study period. The tumors were clearly visible when the first [(18)F]EF5 scan was acquired. After an exponential growth phase, the tumors were imaged again with [(18)F]EF5 and also with (18)F-fluorodeoxyglucose ([(18)F]FDG)., Results: There was a clear correlation between the percentage of tumor growth rate per day and the [(18)F]EF5 uptake in the latter scan (r = 0.766, p = 0.01). The uptake of [(18)F]EF5 in the first scan and the uptake of [(18)F]FDG did not significantly correlate with the tumor growth rate. We also observed considerable variations in the uptake of [(18)F]EF5 between the two scans., Conclusions: The uptake of [(18)F]EF5 in the late phase of exponential tumor growth is associated with the tumor growth rate in mice bearing HNC xenografts.

Background: The purpose of the study was to evaluate the applicability of (18) F-labelled amyloid imaging positron emission tomography (PET) agent [ (18) F]flutemetamol to detect changes in brain beta-amyloid (Aβ) deposition in vivo in APP23, Tg2576 and APPswe-PS1dE9 mouse models of Alzheimer's disease. We expected that the high specific activity of [ (18) F]flutemetamol would make it an attractive small animal Aβ imaging agent., Methods: [ (18) F]flutemetamol uptake in the mouse brain was evaluated in vivo at 9 to 22 months of age with an Inveon Multimodality PET/CT camera (Siemens Medical Solutions USA, Knoxville, TN, USA). Retention in the frontal cortex (FC) was evaluated by Logan distribution volume ratios (DVR) and FC/cerebellum (CB) ratios during the late washout phase (50 to 60 min). [ (18) F]flutemetamol binding to Aβ was also evaluated in brain slices by in vitro and ex vivo autoradiography. The amount of Aβ in the brain slices was determined with Thioflavin S and anti-Aβ1-40 immunohistochemistry., Results: In APP23 mice, [ (18) F]flutemetamol retention in the FC increased from 9 to 18 months. In younger mice, DVR and FC/CB50-60 were 0.88 (0.81) and 0.88 (0.89) at 9 months (N = 2), and 0.98 (0.93) at 12 months (N = 1), respectively. In older mice, DVR and FC/CB50-60 were 1.16 (1.15) at 15 months (N = 1), 1.13 (1.16) and 1.35 (1.35) at 18 months (N = 2), and 1.05 (1.31) at 21 months (N = 1). In Tg2576 mice, DVR and FC/CB50-60 showed modest increasing trends but also high variability. In APPswe-PS1dE9 mice, DVR and FC/CB50-60 did not increase with age. Thioflavin S and anti-Aβ1-40 positive Aβ deposits were present in all transgenic mice at 19 to 22 months, and they co-localized with [ (18) F]flutemetamol binding in the brain slices examined with in vitro and ex vivo autoradiography., Conclusions: Increased [ (18) F]flutemetamol retention in the brain was detected in old APP23 mice in vivo. However, the high specific activity of [ (18) F]flutemetamol did not provide a notable advantage in Tg2576 and APPswe-PS1dE9 mice compared to the previously evaluated structural analogue [(11)C]PIB. For its practical benefits, [ (18) F]flutemetamol imaging with a suitable mouse model like APP23 is an attractive alternative.

Background: An unknown location hampers removal of pancreatic tumours. We studied the effects of enzyme inhibitors on the uptake of 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine ([18F]FDOPA) in the pancreas, aiming at improved imaging of pancreatic adenocarcinoma., Methods: Mice bearing orthotopic BxPC3 pancreatic adenocarcinoma were injected with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) and scanned with positron emission tomography/computed tomography (PET/CT). For [18F]FDOPA studies, tumour-bearing mice and sham-operated controls were pretreated with enzyme inhibitors of aromatic amino acid decarboxylase (AADC), catechol-O-methyl transferase (COMT), monoamine oxidase A (MAO-A) or a combination of COMT and MAO-A. Mice were injected with [18F]FDOPA and scanned with PET/CT. The absolute [18F]FDOPA uptake was determined from selected tissues using a gamma counter. The intratumoural biodistribution of [18F]FDOPA was recorded by autoradiography. The main [18F]FDOPA metabolites present in the pancreata were determined with radio-high-performance liquid chromatography., Results: [18F]FDG uptake was high in pancreatic tumours, while [18F]FDOPA uptake was highest in the healthy pancreas and significantly lower in tumours. [18F]FDOPA uptake in the pancreas was lowest with vehicle pretreatment and highest with pretreatment with the inhibitor of AADC. When mice received COMT + MAO-A inhibitors, the uptake was high in the healthy pancreas but low in the tumour-bearing pancreas., Conclusions: Combined use of [18F]FDG and [18F]FDOPA is suitable for imaging pancreatic tumours. Unequal pancreatic uptake after the employed enzyme inhibitors is due to the blockade of metabolism and therefore increased availability of [18F]FDOPA metabolites, in which uptake differs from that of [18F]FDOPA. Pretreatment with COMT + MAO-A inhibitors improved the differentiation of pancreas from the surrounding tissue and healthy pancreas from tumour. Similar advantage was not achieved using AADC enzyme inhibitor, carbidopa.

Background: We present the electrophilic synthesis of [18F]2β-carbomethoxy-3β-(4-fluoro)tropane [[18F]CFT] and the pharmacological specificity and selectivity of [18F]CFT for monoamine transporters in the brain and peripheral organs of rats. The human radiation dose is extrapolated from the animal data., Methods: [18F]CFT was synthesized by electrophilic fluorination of a stannylated precursor by using post-target-produced [18F]F2 as a fluorinating agent. The ex vivo 18F-activity biodistribution of [18F]CFT in the brain of rats was studied by autoradiography. The binding of [18F]CFT to the monoamine transporters was studied using in vivo blocking experiments with dopamine transporter [DAT], norepinephrine transporter [NET], or serotonin transporter [SERT] inhibitors. In vivo animal positron emission tomography was used as a comparative method to determine tracer kinetics. Human radiation dose was assessed using OLINDA software., Results: The radiochemical yield of [18F]CFT from the initial [18F]F-, decay corrected to the end of bombardment, was 3.2 ± 1.0%. The specific activity [SA] was 14.5 ± 3.4 GBq/μmol, decay corrected to the end of synthesis. Radiochemical purity exceeded 99%. DAT-specific binding was found in the striatum, locus coeruleus, and pancreas. NET-specific binding was found in the locus coeruleus. SERT-specific binding was not found in any of the studied organs. Effective dose equivalent [EDE] estimated for the standard human model was 12.8 μSv/MBq. Effective dose [ED] was 9.17 μSv/MBq., Conclusions: Post-target-produced high-SA [18F]F2 was used to incorporate18F directly into the phenyl ring of [18F]CFT. The final product had high radiochemical and chemical purities and a high SA for DAT and NET studies in vivo. In periphery, [18F]CFT showed a specific uptake in the pancreas. EDE and ED corresponded well with other18F-radioligands.