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Reducing proteinuria is a crucial approach in preventing kidney function loss. Previous preclinical studies indicated that caloric restriction (CR) imposed at a young age protects against age-related proteinuria. However, these studies have not explored CR in established renal disease. Therefore, this study aimed to investigate the impact of CR on established proteinuria. Rats, aged 12 ± 2 weeks, were administered 2.1 mg/kg of Adriamycin. Six weeks after injection, protein excretion was measured, and a [ 13 N]ammonia positron emission tomography (PET) scan was conducted to assess kidney perfusion. After 7 weeks rats were divided into four groups: ad libitum (AL) and CR groups fed either a 12% or a 20% protein diet. All groups were treated for 12 weeks. Blood pressure was measured and a second PET scan was acquired at the end of the study. The animals subjected to CR exhibited a 20.3% decrease in protein excretion (p = 0.003) compared to those in the AL groups. Additionally, blood pressure in the CR group was 21.2% lower (p < 0.001) than in the AL groups. While kidney function declined over time in all groups, the 20% CR group demonstrated the smallest decline. Thus CR effectively reduces urinary protein excretion and lowers blood pressure in rats with established proteinuria., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: The apolipoprotein E-deficient (apoE -/- ) mouse is a well-established model for studying atherosclerosis. However, its small size limits its use in longitudinal positron emission tomography (PET) imaging studies. Recently, the apoE -/- rat has emerged as an alternative. With this study, we investigate the feasibility of using apoE -/- rats as an in vivo model for longitudinal atherosclerotic PET/CT imaging., Results: ApoE -/- rats showed significantly higher [ 18 F]FDG uptake than controls in the aortic arch (+ 18.5%, p < 0.001) and abdominal aorta (+ 31.0%, p < 0.001) at weeks 12, 26, and 51. ApoE -/- rats exhibited hypercholesterolemia, as evidenced by plasma cholesterol levels that were up to tenfold higher, and total hepatic cholesterol levels that were up to threefold higher than the control rats at the end of the study. Fast protein liquid chromatography cholesterol profiling indicated very high levels of pro-atherogenic apoB-containing very low-density lipoprotein and low-density lipoprotein fractions in the apoE -/- rats. Atherosclerotic lesions cover 19.9% of the surface of the aortic arch (p = 0.0013), and there was a significantly higher subendothelial accumulation of ED1-positive macrophages in the abdominal aorta of the apoE -/- rats compared to control rats (Ctrl) (p = 0.01). No differences in neutral sterols were observed but higher levels of bile acids were found in the apoE -/- rats., Conclusion: These data demonstrate early signs of hypercholesterolemia, high levels of bile acids, the development of atherosclerotic lesions, and macrophage accumulation in apoE -/- rats. Therefore, this model shows promise for atherosclerosis imaging studies., (© 2023. The Author(s).)

Fluorine-18-fluorodeoxyglucose ([ 18 F]FDG) positron emission tomography ( 18 F-FDG-PET) is widely used for the detection of inflammatory and infectious diseases. Although this modality has proven to be a useful diagnostic tool, reliable distinction of bacterial infection from sterile inflammation or even from a malignancy remains challenging. Therefore, there is a need for bacteria-specific tracers for PET imaging that facilitate a reliable distinction of bacterial infection from other pathology. The present study was aimed at exploring the potential of 2-[ 18 F]-fluorodeoxysorbitol ([ 18 F]FDS) as a tracer for detection of Enterobacterales infections. Sorbitol is a sugar alcohol that is commonly metabolized by bacteria of the Enterobacterales order, but not by mammalian cells, which makes it an attractive candidate for targeted bacterial imaging. The latter is important in view of the serious clinical implications of infections caused by Enterobacterales. Here we demonstrate that sorbitol-based PET can be applied to detect a broad range of clinical bacterial isolates not only in vitro, but also in blood and ascites samples from patients suffering from Enterobacterales infections. Notably, the possible application of [ 18 F]FDS is not limited to Enterobacterales since Pseudomonas aeruginosa and Corynebacterium jeikeium also showed substantial uptake of this tracer. We conclude that [ 18 F]FDS is a promising tracer for PET-imaging of infections caused by a group of bacteria that can cause serious invasive disease., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Adenosine A 2A and dopamine D 2 receptors in the basal ganglia form heterotetrameric structures that are involved in the regulation of motor activity and neuropsychiatric functions. The present study examines the A 2A receptor-mediated modulation of D 2 receptor binding in vivo using positron emission tomography (PET) with the D 2 antagonist tracer [ 11 C]raclopride. Healthy male Wistar rats ( n = 8) were scanned (60 min dynamic scan) with [ 11 C]raclopride at baseline and 7 days later following an acute administration of the A 2A agonist CGS21680 (1 mg/kg), using a MicroPET Focus-220 camera. Nondisplaceable binding potential (BP ND ) values were calculated using a simplified reference tissue model (SRTM), with cerebellum as the reference tissue. SRTM analysis did not show any significant changes in [ 11 C]raclopride BP ND ( p = 0.102) in striatum after CGS21680 administration compared to the baseline. As CGS21680 strongly affects hemodynamics, we also used arterial blood sampling and a metabolite-corrected plasma input function for compartment modeling using the reversible two-tissue compartment model (2TCM) to obtain the BP ND from the k 3 / k 4 ratio and from the striatum/cerebellum volume of distribution ratio (DVR) in a second group of animals. These rats underwent dynamic [ 11 C]raclopride scans after pretreatment with a vehicle ( n = 5), a single dose of CGS21680 (1 mg/kg, n = 5), or a single dose of the A 2A antagonist KW6002 (1 mg/kg, n = 5). The parent fraction in plasma was significantly higher in the CGS21680-treated group ( p = 0.0001) compared to the vehicle-treated group. GCS21680 administration significantly reduced the striatal k 3 / k 4 ratio ( p < 0.01), but k 3 and k 4 estimates may be less reliable. The BP ND (DVR-1) decreased from 1.963 ± 0.27 in the vehicle-treated group to 1.53 ± 0.55 ( p = 0.080) or 1.961 ± 0.11 ( p = 0.993) after the administration of CGS21680 or KW6002, respectively. Our study suggests that the A 2A agonist CGS21680, but not the antagonist KW6002, may reduce the D 2 receptor availability in the striatum.

Introduction : Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and a diverse range of nonmotor symptoms. Functional relationships between the dopaminergic and histaminergic systems suggest that dual-action pharmaceuticals like AG-0029 (D 2 /D 3 agonist/H 3 antagonist) could ameliorate both the motor and cognitive symptoms of PD. The current study aimed to demonstrate the interaction of AG-0029 with its intended targets in the mammalian brain using positron emission tomography (PET). Methods : Healthy male Wistar rats were scanned with a small-animal PET camera, using either the dopamine D 2 /D 3 receptor ligand [ 11 C]raclopride or the histamine H 3 receptor ligand [ 11 C]GSK-189254, before and after treatment with an intravenous, acute, single dose of AG-0029. Dynamic [ 11 C]raclopride PET data (60 min duration) were analyzed using the simplified reference tissue model 2 (SRTM2) with cerebellum as reference tissue and the nondisplaceable binding potential as the outcome parameter. Data from dynamic [ 11 C]GSK-189254 scans (60 min duration) with arterial blood sampling were analyzed using Logan graphical analysis with the volume of distribution ( V T ) as the outcome parameter. Receptor occupancy was estimated using a Lassen plot. Results : Dopamine D 2/3 receptor occupancies in the striatum were 22.6 ± 18.0 and 84.0 ± 3.5% (mean ± SD) after administration of 0.1 and 1 mg/kg AG-0029, respectively. In several brain regions, the V T values of [ 11 C]GSK-189254 were significantly reduced after pretreatment of rats with 1 or 10 mg/kg AG-0029. The H 3 receptor occupancies were 11.9 ± 8.5 and 40.3 ± 11.3% for the 1 and 10 mg/kg doses of AG-0029, respectively. Conclusions : Target engagement of AG-0029 as an agonist at dopamine D 2 /D 3 receptors and an antagonist at histamine H 3 receptors could be demonstrated in the rat brain with [ 11 C]raclopride and [ 11 C]GSK-189254 PET, respectively. The measured occupancy values reflect the previously reported high (subnanomolar) affinity of AG-0029 to D 2 /D 3 and moderate (submicromolar) affinity to H 3 receptors.

The histamine H 3 receptor has been considered as a target for the treatment of various central nervous system diseases. Positron emission tomography (PET) studies with the radiolabeled potent and selective histamine H 3 receptor antagonist [ 11 C]GSK-189254 in rodents could be used to examine the mechanisms of action of novel therapeutic drugs or to assess changes of regional H 3 receptor density in animal models of neurodegenerative disease. [ 11 C]GSK-189254 was intravenously administered to healthy Wistar rats ( n = 10), and a 60 min dynamic PET scan was carried out. Arterial blood samples were obtained during the scan to generate a metabolite-corrected plasma input function. PET data were analyzed using a one-tissue compartment model (1T2k), irreversible (2T3k) or reversible two-tissue compartment models (2T4k), graphical analysis (Logan and Patlak), reference tissue models (SRTM and SRTM2), and standard uptake values (SUVs). The Akaike information criterion and the standard error of the estimated parameters were used to select the most optimal quantification method. This study demonstrated that the 2T4k model with a fixed blood volume fraction and Logan graphical analysis can best describe the kinetics of [ 11 C]GSK-189254 in the rat brain. SUV 40-60 and the reference tissue-based measurements DVR(2T4k), BP ND (SRTM), and SUV ratio could also be used as a simplified method to estimate H 3 receptor availability in case blood sampling is not feasible.

Background and Aims: Atherosclerosis is a major contributor to global mortality and is accompanied by vascular inflammation and endothelial dysfunction. Perivascular adipose tissue (PVAT) is an established regulator of vascular function with emerging implications in atherosclerosis. We investigated the modulation of aortic relaxation by PVAT in aged rats with apolipoprotein E deficiency (ApoE -/- ) fed a high-fat diet as a model of early atherosclerosis., Methods and Results: ApoE -/- rats (N = 7) and wild-type Sprague-Dawley controls (ApoE +/+ , N = 8) received high-fat diet for 51 weeks. Hyperlipidemia was confirmed in ApoE -/- rats by elevated plasma cholesterol (p < 0.001) and triglyceride (p = 0.025) levels. Early atherosclerosis was supported by increased intima/media thickness ratio (p < 0.01) and ED1-positive macrophage influx in ApoE -/- aortic intima (p < 0.001). Inflammation in ApoE -/- PVAT was characteristic by an increased [18F]FDG uptake (p < 0.01), ED1-positive macrophage influx (p = 0.0003), mRNA expression levels of CD68 (p < 0.001) and IL-1β (p < 0.01), and upregulated iNOS protein (p = 0.011). The mRNAs of MCP-1, IL-6 and adiponectin remained unchanged in PVAT. Aortic PVAT volume measured with micro-PET/CT was increased in ApoE -/- rats (p < 0.01). Maximal endothelium-dependent relaxation (EDR) to acetylcholine in ApoE -/- aortic rings without PVAT was severely impaired (p = 0.012) compared with controls, while ApoE -/- aortic rings with PVAT showed higher EDR than controls. All EDR responses were blocked by L-NMMA and the expression of eNOS mRNA was increased in ApoE -/- PVAT (p = 0.035)., Conclusion: Using a rat ApoE -/- model of early atherosclerosis, we capture a novel mechanism by which inflammatory PVAT compensates severe endothelial dysfunction by contributing NO upon cholinergic stimulation., (Copyright © 2021. Published by Elsevier Inc.)

Statins are 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors that are widely used to prevent cardiovascular diseases. However, a series of pleiotropic mechanisms have been associated with statins, particularly with atorvastatin. Therefore, the assessment of [ 18 F]atorvastatin kinetics with positron emission tomography (PET) may elucidate the mechanism of action of statins and the impact of sexual dimorphism, which is one of the most debated interindividual variations influencing the therapeutic efficacy. [ 18 F]Atorvastatin was synthesized via a previously optimized 18 F-deoxyfluorination strategy, used for preclinical PET studies in female and male Wistar rats ( n = 7 for both groups), and for subsequent ex vivo biodistribution assessment. PET data were fitted to several pharmacokinetic models, which allowed for estimating relevant kinetic parameters. Both PET imaging and biodistribution studies showed negligible uptake of [ 18 F]atorvastatin in all tissues compared with the primary target organ (liver), excretory pathways (kidneys and small intestine), and stomach. Uptake of [ 18 F]atorvastatin was 38 ± 3% higher in the female liver than in the male liver. The irreversible 2-tissue compartment model showed the best fit to describe [ 18 F]atorvastatin kinetics in the liver. A strong correlation (R 2 > 0.93) between quantitative K i (the radiotracer's unidirectional net rate of influx between compartments) and semi-quantitative liver's SUV (standard uptake value), measured between 40 to 90 min, showed potential to use the latter parameter, which circumvents the need for blood sampling as a surrogate of K i for monitoring [ 18 F]atorvastatin uptake. Preclinical assays showed faster uptake and clearance for female rats compared to males, seemingly related to a higher efficiency for exchanges between the arterial input and the hepatic tissue. Due to the slow [ 18 F]atorvastatin kinetics, equilibrium between the liver and plasma concentration was not reached during the time frame studied, making it difficult to obtain sufficient and accurate kinetic information to quantitatively characterize the radiotracer pharmacokinetics over time. Nevertheless, the reported results suggest that the SUV can potentially be used as a simplified measure, provided all scans are performed at the same time point. Preclinical PET-studies with [ 18 F]atorvastatin showed faster uptake and clearance in female compared to male rats, apparently related to higher efficiency for exchange between arterial blood and hepatic tissue.

Arginase hydrolyzes L-arginine and influences levels of polyamines and nitric oxide. Arginase overexpression is associated with inflammation and tumorigenesis. Thus, radiolabeled arginase inhibitors may be suitable PET tracers for staging arginase-related pathophysiologies. We report the synthesis and evaluation of 2 radiolabeled arginase inhibitors, 18 F-FMARS and 18 F-FBMARS, developed from α-substituted-2-amino-6-boronohexanoic acid derivatives. Methods: Arylboronic ester-derived precursors were radiolabeled via copper-mediated fluorodeboronation. Binding assays using arginase-expressing PC3 and LNCaP cells were performed. Autoradiography of lung sections from a guinea pig model of asthma overexpressing arginase and dynamic small-animal PET imaging with PC3-xenografted mice evaluated the radiotracers' specific binding and pharmacokinetics. Results: 18 F-fluorinated compounds were obtained with radiochemical yields of up to 5% (decay-corrected) and an average molar activity of 53 GBq⋅μmol -1 Cell and lung section experiments indicated specific binding that was blocked up to 75% after pretreatment with arginase inhibitors. Small-animal PET studies indicated fast clearance of the radiotracers (7.3 ± 0.6 min), arginase-mediated uptake, and a selective tumor accumulation (SUV, 3.0 ± 0.7). Conclusion: The new 18 F-fluorinated arginase inhibitors have the potential to map increased arginase expression related to inflammatory and tumorigenic processes. 18 F-FBMARS showed the highest arginase-mediated uptake in PET imaging and a significant difference between uptake in control and arginase-inhibited PC3 xenografted mice. These results encourage further research to examine the suitability of 18 F-FBMARS for selecting patients for treatments with arginase inhibitors., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: High protein (HP) diets have been proposed to reduce body weight in humans. The diets are known to alter energy metabolism, which can affect the quality of [ 18 F]FDG PET heart images. In this preclinical study, we therefore explore the impact of a prolonged HP diet on myocardial [ 18 F]FDG uptake., Methods: C57BL/6J (Black six (Bl6)) and apolipoprotein E-deficient ( apoE -/- ) mice were fed chow, a HP diet, or a low protein (LP) diet for 12 weeks. At baseline and after treatment, the animals were injected with 33.0 MBq of [ 18 F]FDG and a 30 min PET/CT scan was made. Myocardial volume and [ 18 F]FDG uptake were quantified using PET and the % of body fat was calculated from CT., Results: Myocardial [ 18 F]FDG uptake was similar for all diets at the follow-up scan but an increase between baseline and follow-up scans was noticed in the LP groups. Myocardial volume was significantly smaller in the C57BL HP group compared to the other Bl6 groups. Body weight increased less in the two HP groups compared to the chow and LP groups. Body fat percentage was significantly higher in the LP groups. This effect was stronger in C57BL mice (28.7%) compared to apoE -/- mice (15.1%)., Conclusions: Myocardial uptake of [ 18 F]FDG in mice is not affected by increased protein intake but [ 18 F]FDG uptake increases when the amount of protein is lowered. A lower body weight and percentage of body fat were noticed when applying a HP diet.

Purpose: Ovarian cancer (OC) leads to poor survival rates mainly due to late stage detection and innate or acquired resistance to chemotherapy. Thus, efforts have been made to exploit the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) to treat OC. However, patients eventually become resistant to these treatments as well. HER2 overexpression contributes to the acquired resistance to ER-targeted treatment. Trastuzumab treatment, on the other hand, can result in increased expression of ER, which, in turn, increases the sensitivity of the tumors towards anti-estrogen therapy. More insight into the crosstalk between ER and HER2 signaling could improve our knowledge about acquired resistance in ovarian cancer. The aim of this study was to evaluate whether PET could be used to detect changes in ER expression induced by HER2-targeted treatment in vivo., Procedures: Male athymic nude mice were subcutaneously (sc) inoculated with 10 6 SKOV3 human ovarian cancer cells (HER2+/ER+). Two weeks after inoculation, tumor-bearing mice were treated intraperitoneally with either vehicle, the HER2 antibody trastuzumab (20 mg/kg, 2×/week), or the HER2-tyrosine kinase inhibitor lapatinib (40 mg/kg, 5 days/week) for 2 weeks. Thereafter, ER expression in the tumor was assessed by PET imaging with 16α-[ 18 F]-fluoro-17β-estradiol ([ 18 F]FES). Tumors were excised for ex vivo ER and HER2 measurement with Western blotting and immunohistochemistry., Results: All treatments led to smaller tumors than vehicle-treated tumors. Higher [ 18 F]FES maximum standardize tumor uptake (SUV max ) was observed in animals treated with trastuzumab (+ 29 %, P = 0.002) or lapatinib (+ 20 %, P = 0.096) than in vehicle-treated controls. PET results were in agreement with ex vivo analyses., Conclusion: FES-PET imaging can detect changes in ER expression induced by HER2-targeted treatment and therefore can be used to investigate the crosstalk between ER and HER2 in a noninvasive manner.

Since the seminal contribution of Rolf Huisgen to develop the [3+2] cycloaddition of 1,3-dipolar compounds, its azide-alkyne variant has established itself as the key step in numerous organic syntheses and bioorthogonal processes in materials science and chemical biology. In the present study, the copper(I)-catalyzed azide-alkyne cycloaddition was applied for the development of a modular molecular platform for medical imaging of the prostate-specific membrane antigen (PSMA), using positron emission tomography. This process is shown from molecular design, through synthesis automation and in vitro studies, all the way to pre-clinical in vivo evaluation of fluorine-18- labeled PSMA-targeting 'F-PSMA-MIC' radiotracers (t 1/2 =109.7 min). Pre-clinical data indicate that the modular PSMA-scaffold has similar binding affinity and imaging properties to the clinically used [ 68 Ga]PSMA-11. Furthermore, we demonstrated that targeting the arene-binding in PSMA, facilitated through the [3+2]cycloaddition, can improve binding affinity, which was rationalized by molecular modeling. The here presented PSMA-binding scaffold potentially facilitates easy coupling to other medical imaging moieties, enabling future developments of new modular imaging agents., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Purpose: [ 18 F]Fluoroethoxybenzovesamicol ([ 18 F]FEOBV) is a radioligand for the vesicular acetylcholine transporter (VAChT), a marker of the cholinergic system. We evaluated the quantification of [ 18 F]FEOBV in rats in control conditions and after partial saturation of VAChT using plasma and reference tissue input models and test-retest reliability., Procedure: Ninety-minute dynamic [ 18 F]FEOBV PET scans with arterial blood sampling were performed in control rats and rats pretreated with 10 μg/kg FEOBV. Kinetic analyses were performed using one- (1TCM) and two-tissue compartmental models (2TCM), Logan and Patlak graphical analyses with metabolite-corrected plasma input, reference tissue Patlak with cerebellum as reference tissue, standard uptake value (SUV) and SUV ratio (SUVR) using 60- or 90-min acquisition. To assess test-retest reliability, two dynamic [ 18 F]FEOBV scans were performed 1 week apart., Results: The 1TCM did not fit the data. Time-activity curves were more reliably estimated by the irreversible than the reversible 2TCM for 60 and 90 min as the influx rate K i showed a lower coefficient of variation (COV, 14-24 %) than the volume of distribution V T (16-108 %). Patlak graphical analysis showed a good fit to the data for both acquisition times with a COV (12-27 %) comparable to the irreversible 2TCM. For 60 min, Logan analysis performed comparably to both irreversible models (COV 14-32 %) but showed lower sensitivity to VAChT saturation. Partial saturation of VAChT did not affect model selection when using plasma input. However, poor correlations were found between irreversible 2TCM and SUV and SUVR in partially saturated VAChT states. Test-retest reliability and intraclass correlation for SUV were good., Conclusion: [ 18 F]FEOBV is best modeled using the irreversible 2TCM or Patlak graphical analysis. SUV should only be used if blood sampling is not possible.

The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D 2 receptor antagonists were used to assess changes in [ 18 F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate ( K i ) was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [ 18 F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted p > 0.07, Cohen's d 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [ 18 F]-FEOBV was significantly higher after haloperidol treatment (adjusted p = 0.022, Cohen's d = 2.51) than in controls. Compared to controls, the AUC of [ 18 F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted p = 0.4, Cohen's d = 1.77) and raclopride (adjusted p = 0.052, Cohen's d = 1.49) treatment, respectively. No changes in the AUC of [ 18 F]-FEOBV were found in the cerebellum (Cohen's d 0.63-0.74). Raclopride treatment nonsignificantly increased K i in the striatum 1.3-fold compared to control rats (adjusted p = 0.1, Cohen's d = 1.1) while it reduced K i in the cerebellum by 28% (adjusted p = 0.0004, Cohen's d = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in K i in the striatum (10%, adjusted p = 1, Cohen's d = 0.44) and a 40-50% lower K i than controls in all other brain regions (adjusted p < 0.0005, Cohen's d = 3.3-4.7). The changes in K i induced by the selective D 2 receptor antagonist raclopride can in part be quantified using [ 18 F]-FEOBV PET imaging. Haloperidol, a nonselective D 2 /σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [ 18 F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [ 18 F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.

In longitudinal PET studies, animals are repeatedly anesthetized which may affect the repeatability of PET measurements. The aim of this study was to assess the effect of anesthesia on the P-gp function as well as the reproducibility of [ 18 F]MC225 PET scans. Thus, dynamic PET scans with blood sampling were conducted in 13 Wistar rats. Seven animals were exposed to isoflurane anesthesia 1 week before the PET scan ("Anesthesia-exposed" PET). A second group of six animals was used to evaluate the reproducibility of measurements of P-gp function at the blood-brain barrier (BBB) with [ 18 F]MC225. In this group, two PET scans were made with a 1 week interval ("Test" and "Retest" PET). Pharmacokinetic parameters were calculated using compartmental models and metabolite-corrected plasma as an input function. "Anesthesia-exposed" animals showed a 28% decrease in whole-brain volume of distribution ( V T ) ( p < 0.001) compared to "Test", where the animals were not previously anesthetized. The V T at "Retest" also decreased (19%) compared to "Test" ( p < 0.001). The k 2 values in whole-brain were significantly increased by 18% in "Anesthesia-exposed" ( p = 0.005) and by 15% in "Retest" ( p = 0.008) compared to "Test". However, no significant differences were found in the influx rate constant K 1 , which is considered as the best parameter to measure the P-gp function. Moreover, Western Blot analysis did not find significant differences in the P-gp expression of animals not pre-exposed to anesthesia ("Test") or pre-exposed animals ("Retest"). To conclude, anesthesia may affect the brain distribution of [ 18 F]MC225 but it does not affect the P-gp expression or function.

Purpose: An important issue in rodent imaging is the question whether a mixed population of male and female animals can be used rather than animals of a single sex. For this reason, the present study examined the test-retest stability of positron emission tomography (PET) with 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) in male rats and female rats at different phases of the estrous cycle., Procedures: Long-Evans rats (age 1 year) were divided into three groups: (1) males (n = 6), (2) females in metestrous (low estrogen levels, n = 9), and (3) females in proestrous (high estrogen levels, n = 7). Two standard [ 18 F]FDG scans with rapid arterial blood sampling were made at an interval of 10 days in subjects anesthetized with isoflurane and oxygen. Body temperature, heart rate, and blood oxygenation were continuously monitored. Regional cerebral metabolic rates of glucose were calculated using a Patlak plot with plasma radioactivity as input function., Results: Regional metabolic rate of glucose (rCMR glucose ) in male and female rats, or [ 18 F]FDG uptake in females at proestrous and metestrous, was not significantly different, but females showed significantly higher standardized uptake values (SUVs) and Patlak flux than males, particularly in the initial scan. The relative difference between the scans and the test-retest variability (TRV) were greater in females than in males. Intra-class correlation coefficients (ICCs) of rCMR glucose , SUV, normalized SUV, and glucose flux were good to excellent in males but poor to moderate in females., Conclusions: Based on these data for [ 18 F]FDG, the mixing of sexes in imaging studies of the rodent brain will result in an impaired test-retest stability of PET data and a need for larger group sizes to maintain statistical power in group comparisons. The observed differences between males and females do not indicate any specific gender difference in cerebral metabolism but are related to different levels of non-radioactive glucose in blood plasma during isoflurane anesthesia.

The estrogen receptor (ER) is a target for endocrine therapy in breast cancer patients. Individual quantification of ERα and ERβ expression, rather than total ER levels, might enable better prediction of the response to treatment. We recently developed the tracer 2- 18 F-fluoro-6-(6-hydroxynaphthalen-2-yl)pyridin-3-ol ( 18 F-FHNP) for assessment of ERβ levels with PET. In the current study, we investigated several pharmacokinetic analysis methods to quantify changes in ERβ availability with 18 F-FHNP PET. Methods: Male nude rats were subcutaneously inoculated in the shoulder with ERα/ERβ-expressing SKOV3 human ovarian cancer cells. Two weeks after tumor inoculation, a dynamic 18 F-FHNP PET scan with arterial blood sampling was acquired from rats treated with vehicle or various concentrations of estradiol (nonspecific ER agonist) or genistein (ERβ-selective agonist). Different pharmacokinetic models were applied to quantify ERβ availability in the tumor. Results: Irreversible-uptake compartmental models fitted the kinetics of 18 F-FHNP uptake better than reversible models. The irreversible 3-tissue-compartment model, which included both the parent and the metabolite input function, gave results comparable to those of the irreversible 2-tissue-compartment model with only a parent input function, indicating that radioactive metabolites contributed little to the tumor uptake. Patlak graphical analysis gave metabolic rates ( K i , the irreversible uptake rate constant) comparable to compartment modeling. The K i values correlated well with ERβ expression but not with ERα, confirming that K i is a suitable parameter to quantify ERβ expression. SUVs at 60 min after tracer injection also correlated ( r 2 = 0.47; P = 0.04) with ERβ expression. A reduction in 18 F-FHNP tumor uptake and K i values was observed in the presence of estradiol or genistein. Conclusion: 18 F-FHNP PET enables assessment of ERβ availability in tumor-bearing rats. The most suitable parameter to quantify ERβ expression is the K i However, a simplified static imaging protocol for determining the SUVs can be applied to assess ERβ levels., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose ( 18 F-FDG) can be applied to detect infection and inflammation. However, it was so far not known to what extent bacterial pathogens may contribute to the PET signal. Therefore, we investigated whether clinical isolates of frequently encountered bacterial pathogens take up 18 F-FDG in vitro, and whether FDG inhibits bacterial growth as previously shown for 2-deoxy-glucose. 22 isolates of Gram-positive and Gram-negative bacterial pathogens implicated in fever and inflammation were incubated with 18 F-FDG and uptake of 18 F-FDG was assessed by gamma-counting and µPET imaging. Possible growth inhibition by FDG was assayed with Staphylococcus aureus and the Gram-positive model bacterium Bacillus subtilis. The results show that all tested isolates accumulated 18 F-FDG actively. Further, 18 F-FDG uptake was hampered in B. subtilis pts mutants impaired in glucose uptake. FDG inhibited growth of S. aureus and B. subtilis only to minor extents, and this effect was abrogated by pts mutations in B. subtilis. These observations imply that bacteria may contribute to the signals observed in FDG-PET infection imaging in vivo. Active bacterial FDG uptake is corroborated by the fact that the B. subtilis phosphotransferase system is needed for 18 F-FDG uptake, while pts mutations protect against growth inhibition by FDG.