Peak Of Radioactivity Research Articles

Dynamic neuroreceptor positron emission tomography in non-anesthetized rats using point source based motion correction: A feasibility study with [11C]ABP688

To prevent motion artifacts in small animal positron emission tomography (PET), animals are routinely scanned under anesthesia or physical restraint. Both may potentially alter metabolism and neurochemistry. This study investigates the feasibility of fully awake acquisition and subsequent absolute quantification of dynamic brain PET data via pharmacokinetic modelling in moving rats using the glutamate 5 receptor radioligand [11C]ABP688 and point source based motion correction. Five male rats underwent three dynamic [11C]ABP688 PET scans: two test-retest awake PET scans and one scan under anesthesia for comparison. Specific radioligand binding was determined via the simplified reference tissue model (reference: cerebellum) and outcome parameters BPND and R1 were evaluated in terms of stability and reproducibility. Test-retest measurements in awake animals gave reliable results with high correlations of BPND (y = 1.08 × −0.2, r = 0.99, p < 0.01) and an acceptable variability (mean over all investigated regions 15.7 ± 2.4%). Regional [11C]ABP688 BPNDs under awake and anesthetized conditions were comparable although in awake scans, absolute radioactive peak uptakes were lower and relative blood flow in terms of R1 was higher. Awake small animal PET with absolute quantification of neuroreceptor availability is technically feasible and reproducible thereby providing a suitable alternative whenever effects of anesthesia are undesirable, e.g. in sleep research.

Synthesis and preclinical evaluation of [11C]uPSEM792 for PSAM4-GlyR based chemogenetics

Chemogenetic tools are designed to control neuronal signaling. These tools have the potential to contribute to the understanding of neuropsychiatric disorders and to the development of new treatments. One such chemogenetic technology comprises modified Pharmacologically Selective Actuator Modules (PSAMs) paired with Pharmacologically Selective Effector Molecules (PSEMs). PSAMs are receptors with ligand-binding domains that have been modified to interact only with a specific small-molecule agonist, designated a PSEM. PSAM4 is a triple mutant PSAM derived from the α7 nicotinic receptor (α7L131G,Q139L,Y217F). Although having no constitutive activity as a ligand-gated ion channel, PSAM4 has been coupled to the serotonin 5-HT3 receptor (5-HT3R) and to the glycine receptor (GlyR). Treatment with the partner PSEM to activate PSAM4-5-HT3 or PSAM4-GlyR, causes neuronal activation or silencing, respectively. A suitably designed radioligand may enable selective visualization of the expression and location of PSAMs with positron emission tomography (PET). Here, we evaluated uPSEM792, an ultrapotent PSEM for PSAM4-GlyR, as a possible lead for PET radioligand development. We labeled uPSEM792 with the positron-emitter, carbon-11 (t1/2 = 20.4 min), in high radiochemical yield by treating a protected precursor with [11C]iodomethane followed by base deprotection. PET experiments with [11C]uPSEM792 in rodents and in a monkey transduced with PSAM4-GlyR showed low peak radioactivity uptake in brain. This low uptake was probably due to high polarity of the radioligand, as evidenced by physicochemical measurements, and to the vulnerability of the radioligand to efflux transport at the blood–brain barrier. These findings can inform the design of a more effective PSAM4 based PET radioligand, based on the uPSEM792 chemotype.

A 'new' estrogen metabolite: an epoxide of estrone as a sulfated steroid.

Current heightened recognition of the importance of sulfated steroids led to the examination of conjugates in media from incubations of estrogens in tissues from the reproductive tract of stallions. Previously, we had reported a 'new' unidentified metabolite of estrone (E1) and [3H]-E1, located between 17β-estradiol (E2) and E1 reference standards on chromatography (HPLC) and identified tentatively as a stable 5α,6α-estrone epoxide. Stallion tissues were minced and incubated for 2 h with [3H]-E1 (1 × 106 cpm). Solid-phase extraction of unconjugated and conjugated steroids from media was followed by liquid scintillation counting (LSC), where radioactivity was mostly in the conjugate fractions (>80%). HPLC of conjugated steroids used an isocratic solvent system of acetonitrile/water (8:92) at 700 µL/min with detection by LSC. A radioactive peak between reference standards of E1 and E2 sulfates was examined, after solvolysis, in a second solvent system. Sulfated steroids yielded largely E1, whereas acid treatment of the unconjugated E1 epoxide had earlier formed 6α-OH-E1 almost exclusively. With sulfatase enzyme, at neutral pH, radioactivity was also seen mostly as E1 with trace amounts of polar material. Reduction with KBH4, however, led also to desulfation; radioactivity had alignment with E2 but even more had low retention times as for 6α/6β-OH-E2. These findings point to a different hydrolysis for desulfation; even more, they reveal an additional oxygen atom at C6 and are supportive of biological formation of 5α,6α-epoxides of E1 and E2. As possible alternatives to catechol estrogens, implicated in cancer, the 'new' estrogen metabolites and their sulfated forms may have special interest.

A closer look at the synthesis of 2-[18F]fluoroethyl tosylate to minimize the formation of volatile side-products

Background2-[18F]Fluoroethyltosylate ([18F]FEtOTs) is a well-known 18F-fluoroalkylating agent widely used to synthesize radiotracers for positron emission tomography. The widespread use of [18F]FEtOTs is due in part to its low volatility when compared to other halide and sulfonate building blocks. In this work, the radioactive volatile side-products formed during the synthesis of [18F]FEtOTs were identified and characterized for the first time, and an optimization of the reaction conditions to minimize their formation was proposed.ResultsIn order to characterize the volatiles produced during [18F]FEtOTs synthesis, the reaction mixtures of both cold FEtOTs and [18F]FEtOTs were co-injected onto the HPLC system. The radioactive peaks corresponding to the volatile compounds were collected, analyzed through headspace gas chromatography mass spectrometry sampler (HS-GC–MS) and identified as vinyl fluoride ([19F]VF) and 2-fluoroethanol ([19F]FEOH). By using a rotatable central composite design with a two-level full factorial core of two factors (22), it was determined that temperature and time are independent variables which affect the generation of [18F]VF and [18F]FEOH during the radiosynthesis of [18F]FEtOTs. In addition, in order to reduce the formation of the volatiles ([18F]VF and [18F]FEOH) and increase the yield of [18F]FEtOTs, it was demonstrated that the molar ratio of base to precursor must also be considered.Conclusion[18F]VF and [18F]FEOH are volatile side-products formed during the radiosynthesis of [18F]FEtOTs, whose yields depend on the reaction time, temperature, and the molar ratio of base to precursor. Therefore, special care should be taken during the radiosynthesis and subsequent reactions using [18F]FEOTs in order to avoid environmental contamination and to improve the yield of the desired products.

A 75-year history of microplastic fragment accumulation rates in a semi-enclosed hypoxic basin

Plastic budgets in the marine environment and their long-term trends are yet to be fully understood. Measuring the accumulation rates in bottom sediments is crucial to solving the riddle of missing ocean plastics. Previous studies based on coastal sediment cores have found that accumulation rates have increased with increases in plastic production and/or regional populations. However, the correlations between the rates and bioactivities or ocean dynamics, which are crucial for modeling the microplastic sinking process, have not been examined. We revealed a 75-year microplastic fragment (0.3–5.0 mm) accumulation rate history in a hypoxic basin, Beppu Bay, Japan, based on multi-core analysis and 210Pb dating of the sediment which was cross-checked by time control with 137Cs radioactivity peaks. We found that a long-term linear increasing trend with an approximately 20-year variation overlapped with significant peaks around 1990 and 2014 with the first polypropylene microplastic fragment detected from a 1958.8–1961.0 CE sediment layer. The maximum rate was 203 pieces m−2 y−1 with an abundance of 86 pieces kg−1-dry in 2014. Smaller fragments in the size range of 0.3–2.0 mm have been consistently dominant in terms of the accumulation rate throughout the 1955–2015 period, accounting for 85.3 % of the total accumulation rate. The three major polymers (polyethylene, polypropylene, and polystyrene) accounted for 96.6 % of the total rate. The rate was highly and positively correlated with the chlorophyll-a accumulation rate and concentration in the sediment. Based on the microplastic accumulation rates and concentration in the seawater, the mean sinking velocity of microplastics was estimated to be in the order of 101 m d−1. Our results will contribute to significant progress in modeling the microplastic sinking process by offering the first field measurement-based mean sinking velocity and significant correlations between the rate and bioactivity-related signals.

Radiosynthesis and initial preclinical evaluation of [11C]AZD1283 as a potential P2Y12R PET radiotracer

IntroChronic neuroinflammation and microglial dysfunction are key features of many neurological diseases, including Alzheimer's Disease and multiple sclerosis. While there is unfortunately a dearth of highly selective molecular imaging biomarkers/probes for studying microglia in vivo, P2Y12R has emerged as an attractive candidate PET biomarker being explored for this purpose. Importantly, P2Y12R is selectively expressed on microglia in the CNS and undergoes dynamic changes in expression according to inflammatory context (e.g., toxic versus beneficial/healing states), thus having the potential to reveal functional information about microglia in living subjects. Herein, we identified a high affinity, small molecule P2Y12R antagonist (AZD1283) to radiolabel and assess as a candidate radiotracer through in vitro assays and in vivo positron emission tomography (PET) imaging of both wild-type and total knockout mice and a non-human primate. MethodsFirst, we evaluated the metabolic stability and passive permeability of non-radioactive AZD1283 in vitro. Next, we radiolabeled [11C]AZD1283 with radioactive precursor [11C]NH4CN and determined stability in formulation and human plasma. Finally, we investigated the in vivo stability and kinetics of [11C]AZD1283 via dynamic PET imaging of naïve wild-type mice, P2Y12R knockout mouse, and a rhesus macaque. ResultsWe determined the half-life of AZD1283 in mouse and human liver microsomes to be 37 and > 160 min, respectively, and predicted passive CNS uptake with a small amount of active efflux, using a Caco-2 assay. Our radiolabeling efforts afforded [11C]AZD1283 in an activity of 12.69 ± 10.64 mCi with high chemical and radiochemical purity (>99%) and molar activity of 1142.84 ± 504.73 mCi/μmol (average of n = 3). Of note, we found [11C]AZD1283 to be highly stable in vitro, with >99% intact tracer present after 90 min of incubation in formulation and 60 min of incubation in human serum. PET imaging revealed negligible brain signal in healthy wild-type mice (n = 3) and a P2Y12 knockout mouse (0.55 ± 0.37%ID/g at 5 min post injection). Strikingly, high signal was detected in the liver of all mice within the first 20 min of administration (peak uptake = 58.28 ± 18.75%ID/g at 5 min post injection) and persisted for the remaining duration of the scan. Ex vivo gamma counting of mouse tissues at 60 min post-injection mirrored in vivo data with a mean %ID/g of 0.9% ± 0.40, 0.02% ± 0.01, and 106 ± 29.70% in the blood, brain, and liver, respectively (n = 4). High performance liquid chromatography (HPLC) analysis of murine blood and liver metabolite samples revealed a single radioactive peak (relative area under peak: 100%), representing intact tracer. Finally, PET imaging of a rhesus macaque also revealed negligible CNS uptake/binding in monkey brain (peak uptake = 0.37 Standard Uptake Values (SUV)). ConclusionDespite our initial encouraging liver microsome and Caco-2 monolayer data, in addition to the observed high stability of [11C]AZD1283 in formulation and human serum, in vivo brain uptake was negligible and rapid accumulation was observed in the liver of both naïve wildtype and P2Y12R knockout mice. Liver signal appeared to be independent of both metabolism and P2Y12R expression due to the confirmation of intact tracer in this tissue for both wildtype and P2Y12R knockout mice. In Rhesus Macaque, negligible uptake of [11C]AZD1283 brain indicates a lack of potential for translation or its further investigation in vivo. P2Y12R is an extremely promising potential PET biomarker, and the data presented here suggests encouraging metabolic stability for this scaffold; however, the mechanism of liver uptake in mice should be elucidated prior to further analogue development.

Combination of high specific activity carbon-14 labeling and high resolution mass spectrometry to study pesticide metabolism in crops: Metabolism of cycloxaprid in rice.

The study of pesticide metabolism in crops is critical for assessing the mode of action and environmental risks of pesticides. However, the study of pesticide metabolism in crops is usually complicated and it is often a daunting challenge to accurately screen the metabolites of novel pesticides in complex matrices. This study demonstrated a combined use of high-specific activity carbon-14 labeling and high-resolution mass spectrometry (HSA-14C-HRMS) for metabolism profiling of a novel neonicotinoid cycloxaprid in rice. By generating the characteristic radioactive peaks on the liquid chromatogram, the use of 14C can eliminate the severe interference of complex matrices and quickly probe target compounds; by producing ion pairs with unique abundance ratios on HRMS, high-specific activity labeling can effectively exclude false matrix positives and promote the elucidation of metabolite structure. The structures of 15 metabolites were identified, three of which were further confirmed by authentic standards. Based on these metabolites, a metabolic profile of cycloxaprid was established, which includes denitrification, demethylation, imidazolidine hydroxylation and ring cleavage olefin formation, oxidation and carboxylation reactions. The strategy of combining high-specific activity 14C labeling and HRMS offers unique advantages and provides a powerful solution for profiling unknown metabolites of novel pesticides in complex matrices, especially when traditional non-labeling methods are not feasible.

Absorption, metabolism and excretion of once-weekly somapacitan, a long-acting growth hormone derivative, after single subcutaneous dosing in human subjects

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative in clinical development for once-weekly administration in patients with adult GH deficiency (AGHD) and children with GH deficiency (GHD). To date, the use of somapacitan in AGHD or severe AGHD has been approved in the USA and Japan, respectively. This study (ClinicalTrials.gov, NCT02962440) investigated the absorption, metabolism and excretion, as well as the pharmacokinetics (PK), of tritium-labelled somapacitan ([3H]-somapacitan). Seven healthy males received a single subcutaneous dose of 6 mg somapacitan containing [3H]-somapacitan 20 MBq. Blood, serum, plasma, urine, faeces, and expired air were collected for radioactivity assessment. Metabolites were identified and quantified in plasma and urine collected. The PK of plasma components were determined, and the radioactive peaks of the most abundant plasma metabolites and urine metabolites were selected for analysis. Twenty-eight days after dosing, 94.0% of the administered dose was recovered as [3H]-somapacitan-related material, most of which was excreted in urine (80.9%); 12.9% was excreted in faeces, and an insignificant amount (0.2%) was exhaled in expired air. PK properties of [3H]-somapacitan-related material appeared to be consistent across plasma, serum and blood. Three abundant plasma metabolites (P1, M1 and M1B) and two abundant urine metabolites (M4 and M5) were identified. The total exposure of intact somapacitan accounted for 59% of the total exposure of all somapacitan-related material, P1 accounted for 21% and M1 plus M1B accounted for 12%. M4 and M5 were the most abundant urine metabolites and accounted for 37% and 8% of the dosed [3H]-somapacitan radioactivity, respectively. No intact somapacitan was found in excreta. Two subjects had six adverse events (AEs); all were mild in severity and unlikely to be related to trial product. The majority of dosed [3H]-somapacitan (94%) was recovered as excreted metabolites. Urine was the major route for excretion of somapacitan metabolites, followed by faeces, and exhalation in expired air was negligible. The low molecular weights of identified urine metabolites demonstrate that somapacitan was extensively degraded to small residual fragments that were excreted (fully biodegradable). The extensive metabolic degradation and full elimination of metabolites in excreta were the major clearance pathways of somapacitan and the key elements in its biological fate. A single dose of 6 mg somapacitan (containing [3H]-somapacitan) in healthy male subjects was well tolerated with no unexpected safety issues identified.

Drowning unconformities on presalt carbonate platforms – Examples from the Itapema Formation (Lower Cretaceous), Santos Basin, offshore Brazil

Drowning unconformities are surfaces characterized on seismic data by high amplitude contrast between deepwater and shallow water facies. Such surfaces are created by the covering of the platform by onlapping siliciclastic sediments or other non-platform material. The key aspect of this paper is the application of the drowning unconformity concept, commonly used in marine settings, to a more restrictive one: the coquinas of the Itapema Formation, in the pre-salt succession of the Santos Basin (Brazil). In the studied area the sequence boundaries of the deposits related to the Itapema Formation are often associated with high reflectivity seismic horizons, which are tied to radioactive peaks of low-energy sedimentary facies in the gamma ray logs and also to the siliciclastic supply rate increase. However, the stratigraphic significance of these reflectors still lacks further investigation and an adequate description. In this way, it is proposed that the space-time filling of the Itapema Formation occurred by the successive migration of proximal facies towards the structural highs, under continuous accommodation space generation conditions and high carbonate production rate, with the depocenters limited by rapid expansions of the basin. The results presented here, therefore, suggest that the sedimentary record of this section was punctuated by instantaneous transgressive surfaces that altered the ecological accommodation, forcing the backstepping of the coquina deposits and the development of a drowning unconformity in the final stage of the Itapema Formation deposition. This configuration produced at the top of this unit a specific facies association characterized by packstones and mudstones composed of micritized grains, which increase in volume and thickness towards the structural lows and tend to be thinner on the way up to the structural highs, where they may be eroded by the Pre-Alagoas Unconformity. The correct identification of such surfaces is essential for understanding the sedimentary filling of the studied area. Depending on which surface is mapped, they may be related to different processes and occur in opposite positions in the base-level cycles. Thus, we propose the existence of two surfaces at the end of the deposition of the Itapema Formation. The first limits the top of the coquinas and is represented by the contrast of low-energy sediments (packstones and micritized mudstones) and the coquinas deposits, configuring the platform drowning itself. The second one, in turn, is understood here as the Pre-Alagoas Unconformity, a subaerial unconformity associated with the regional platform exposure, developed after the drowning events recognized here.

Evaluation of toxicity of an organophosphate pesticide (Nogos) on behavior of the walking catfish (Clarias batrachus ) and it’s translocation in rice-fish ecosystem

The Present study investigated the toxic effects of the pesticide Nogos on the walking catfish Clarias batrachus, and its translocation and residual accumulation in a pesticide administrated rice-fish ecosystem under laboratory conditions. The experiment was conducted in aquaria containing soil collected from the paddy. Nogos was applied at five concentrations such as 0.085 ppm. 0.170 ppm, 0.255 ppm, 0.340 ppm, 0.510 ppm and 0.595ppm. A control was maintained without Nogos. An LC50 was obtained at a concentration of 0.31 ppm Nogos. Nogos at a concentration of 0.595 ppm showed LC100 to the fish while lower concentrations of 0.085 ppm did not induce any mortality. Some behavioral changes noticed were: rapid opercular movement, jumping, jerking, erratic and circular movement, loss of equilibrium, leaching of mucous through anus, immobility and resting on the corners of the test aquarium, development of red spots on the dorsal surface, white spots on the abdomen. Maximum radioactivity was observed in water on day 2 (1.1 µg/g) of application of the pesticide. Soil sample showed peak radioactivity 0.55 µg/g on day 12 of application and thereafter declined slowly to background level by day 90 of pesticide application. Paddy root and shoot showed highest activity on day 24 (0.24 µg/g) and day 24 (0.20 µg/g), respectively.

Reconstruction of sedimentation rates based on the chronological framework of Lake Pykara, Tamil Nadu, India.

This work presents a piece of initial information about the estimation of the sedimentation rate for Lake Pykara. In this investigation, a chronological sequence of sediment core was set up dependent on 137Cs and 210Pbex analysis to study sediment accumulation rates in Lake Pykara. Caesium-137 (Cs) is an artificial radionuclide and is regularly utilized in building up the chronology of lake sediments in the Anthropocene period. The unsupported 210Pb profile shows a non-exponential decline of 210Pb activity with sediment depth. Sedimentation rates dependent on global atmospheric nuclear weapon maximum fallout of 137Cs (1963) bolster the utilization of the consistent rate of 210Pb supply (CRS) model in core sediments. The geochronology studies of the core were performed using the 137Cs method, to evaluate the model of time changes in the sediment. The 137Cs radioactivity was resolved directly by gamma spectrometry and fluctuated from 13.11 ± 1.3Bqkg-1 for top layers to 1.21 ± 0.1Bqkg-1 for the bottom of the core. Two trademark peaks of 137Cs radioactivity identified with the global fallouts after atomic weapons testing and the Chernobyl mishap were observed and used to affirm the 210Pb dating method. Radioactivity of 210Pbex ranged from 8.00 ± 1.0 to 1.40 ± 0.1Bqkg-1. The mean sedimentation rate evaluated from both models was 0.71 ± 0.06cmyear-1, while the estimated age of Lake Pykara was 514.08years (137Cs) and 521.43years (210Pbex), respectively.

Renal Artery Stenosis Presenting at Sudden Flash Pulmonary Edema in a Patient with Solitary Kidney

Flash pulmonary edema is characterized by a sudden episode of dyspnea resulting from acute pulmonary venous congestion, which resolves rapidly. We report a case of renal artery stenosis presenting as flash pulmonary edema in a patient with solitary kidney treated by angioplasty with stent implantation. A 75-year-old man with solitary kidney visited the emergency room with acute shortness of breath. His blood pressure had risen to 206/90 mmHg and a chest radiograph revealed pulmonary edema. Echocardiography and coronary arteriography showed no clear abnormalities, but abdominal computed tomography revealed severe focal stenosis in the left proximal renal artery. A captopril renal scan found that the time to peak and half-time of radioactivity were delayed in the left kidney. Percutaneous transluminal angioplasty was performed, followed by stent implantation. After this procedure, the stenotic segment was completely dilated and blood pressure returned to the normal range.

Dating of an alpine ice core from the interior of the Tibetan Plateau

Accurate archive-based paleoclimate reconstruction requires precise dating. However, the dating of mid- and low-latitude alpine ice cores is in challenge, in particular for the lower parts of ice cores. Here, we present a new dating work for a 109 m ice core collected to bedrock from the Qiangtang No. 1 glacier, central Tibetan Plateau. Annual layer counting based on seasonal indicators, in combination with absolute dating of radioactivity peaks, indicates that the upper part (0–79 m) captures a period of 678 years from 1334–2011 AD, with an uncertainty of ±20 years at 79 m. In the lower part (79–109 m), we dated by visible annual layer thickness-depth relationships and found the lower ice core captures 665 years of deposition and can be dated back to 669 ± 66 AD at 109 m. This new method reduces the ambiguity of utilizing glacier flow models that have been widely used in previous study. On the presence of observable optical annual layers, the polynomial fitting method based on annual layer thickness-depth relationships is a superior method to obtain reliable chronology in the lower parts. Furthermore, this method has the potential to improve the dating of other alpine ice cores with similar settings.

Response of Gamma-Ray Spectrum During Ockhi Cyclone

Cyclone Ockhi hit Sri Lanka and southern parts of India in Nov-Dec 2017 with a devastating social impact. The present paper reports that the cyclone had a significant effect on the γ-ray flux measured by NaI (Tl) detector. An overall decrease is observed in the γ-ray flux during the passage of cyclone; however, a detailed investigation revealed that different energies show varying results. In the energy range between 250 keV – 450 keV, a decrease up to ~ 14% is observed, whereas an increase up to ~ 45% is observed in the energy range between 600 keV – 2.7 MeV. The energies above 2.7 MeV do not show any change. This is the first-ever observation of the varying effects of the cyclone with the energy bands of the γ-ray spectrum. We found that the increase observed in the energy range of 600 keV – 2.7 MeV is primarily associated with the increase in the terrestrial radioactivity (peaks of Rn-222 daughters), which is due to the rainfall brought over by the cyclone. The high energy γ-rays originating from cosmic ray are not affected due to the cyclone. The study indicates that the decrease in the lower energy range of the γ-ray flux could be due to the attenuation caused by the increased tropospheric air-mass associated with the cyclone over the observation site.

Development of a thin layer chromatography method for plasma correction of [18F]fluorocholine metabolites in positron emission tomography quantification studies in humans

IntroductionAfter its intravenous injection, [18F]fluorocholine is oxidized by choline-oxidase into its main plasma metabolite, [18F]fluorobetaine. If PET kinetic modeling quantification of [18F]fluorocholine uptake is intended, the plasma input time-activity-curve of the parent tracer must be obtained, i.e., the fraction of the total plasma radioactivity corresponding to the nonmetabolized [18F]fluorocholine at each time has to be known. Hence our aim was to develop an easy-routine Thin-Layer-Chromatography (TLC) method to separate and quantify the relative fractions of [18F]fluorocholine and [18F]fluorobetaine as a function of time during PET imaging in humans. MethodsFirst, we tested several combinations of solvents systems and layers to select the one showing the best resolution on non-radioactive standards. Thereafter, [18F]fluorobetaine was obtained through chemical oxidation of an [18F]fluorocholine sample at diferent incubation times and we applied the selected TLC-system to aliquots of this oxidation solution, both in a saline and in human deproteinized plasma matrices. The plates were detected by a radio-TLC-scanner. This TLC-system was finally applied to arterial plasma samples from 9 patients with high-grade-glioma undergoing brain PET imaging and a parent fraction curve was obtained in each of them. ResultsA TLC-system based on Silica-Gel-60//MeOH-NH3 was selected from the choline/betaine non-radioactive standards assay. Radiochromatograms of [18F]fluorocholine oxidation solution yielded two separated and well-defined peaks, Rf = 0,03 ([18F]fluorocholine) and Rf = 0.78 (18F]fluorobetaine) consistent with those observed on non-radioactive standards. During the oxidation, the [18F]fluorocholine radioactivity peak decreased progressively at several incubation times, while the other peak ([18F]fluorobetaine) increased accordingly. The mean values of the parent fraction of [18F]fluorocholine of the 9 patients studied (mean+/-SD) were 94% ± 6%, 58% ± 15%, 43% ± 10%, 39% ± 6% and 37% ± 6% at 2.8 min, 5.8 min, 8.8 min, 11.7 min and 14.7 min post-injection, respectively. ConclusionsWe have developed a TLC-system, easy to perform in a standard radiopharmacy unit, that enables the metabolite correction of arterial input function of [18F]fluorocholine in patients undergoing PET oncologic quantitative imaging.

A phase I study investigating the absorption, metabolism, and excretion of [14C] anlotinib in patients with advanced refractory solid tumors.

e14701 Background: Anlotinib is a novel oral multi-targeted receptor tyrosine kinase inhibitor, which selectively inhibits VEGFR2/3, FGFR1-4, PDGFR α/β, c-Kit, and Ret, and has shown antitumor activity in patients with advanced refractory solid tumors. The human plasma pharmacokinetics of anlotinib have been described previously, but detailed analyses of the absorption, metabolism and excretion pathways of anlotinib have not yet been published. Methods: Six male patients were divided into two groups, one group included two patients was performed by 13.51mg Anlotinib hydrochloride and 0.64 mg/80 μCi [14C] anlotinib hydrochloride and the rest four patients in another group received 13.19mg anlotinib hydrochloride and 0.96mg/120 μCi [14C] anlotinib hydrochloride, followed by collection of blood, urine, and fecal samples. The primary outcomes of study were absorption, metabolism, and excretion of [14C] anlotinib and the second outcomes were efficacy and safety. Results: In plasma, the average time of total plasma radioactivity peak (Tmax) was 4.42h and the average peak concentration (Cmax) was 18.80 ng Eq./g. The average value of AUC last was 4071 h∙ng Eq./g, AUC0-∞ was 13555 h∙ng Eq./g, and MRT0-t was 145h. The average recovery rate of total radioactivity in urine and feces was 62.03%. Prototype drugs and metabolites were mainly excreted through feces, accounting for 48.52% of the administered dose, otherwise rine excretion accounted for 13.51%. The liver and kidney were the main drug excretion organs. Five patients developed adverse reactions, and one person developed SAE. Three of study population were assessed as stable disease (SD), two with partial response (PR), and one had progressive disease (PD). Conclusions: Anlotinib showed a favourable pharmacokinetic profile with high absolute bioavailability and an extensive hepatic metabolism. The adverse events and efficacy were as expected. Clinical trial information: CTR20160329.

Metabolism of 4-methylimidazole in Fischer 344 rats and B6C3F1 mice

4-Methylimidazole (4-MeI) is a widely used chemical, also identified as a by-product of heating foods. In cancer bioassays, 4-MeI induced lung tumors in mice, but not in rats. To establish if metabolic differences could explain species difference in carcinogenicity, this study investigated metabolism of 4-MeI in rat and mouse lung and liver microsomes and S-9 fractions, and in vivo in rats and mice. No metabolites were detected in rat or mouse lung and liver microsomes, or lung S-9 fractions. Male and female F-344 rats and B6C3F1 mice were administered 50 and 150 mg/kg [14C] 4-MeI by gavage. Excreta, exhaled CO2 and volatiles were collected for 48 h. Elimination was mainly via urine, with 79–89% of the radioactivity in urine in rats and 41–70% in mice. Most of the radioactivity (71–88%) in urine was unchanged 4-MeI. Additional radioactive peaks (the largest metabolite was 8–18%) were characterized by LC-MS/MS as 4-hydroxymethylimidazole, its glucuronide, and other oxidized products, including methylhydantoin. 4-MeI was largely excreted unchanged in rats and mice with limited oxidative metabolism and conjugation. 4-MeI was not oxidized in subcellular fractions from rat and mouse lung and liver. Overall, the metabolism of 4-MeI appeared similar between rats and mice.

Whole Body PET Imaging with a Norepinephrine Transporter Probe 4-[18F]Fluorobenzylguanidine: Biodistribution and Radiation Dosimetry.

4-[18F]Fluorobenzylguanidine ([18F]PFBG) is a positron emission tomography (PET) probe for non-invasive targeting of the norepinephrine transporter. The aim of this study was to assess uptake and distribution characteristics of this PET probe. Three cynomolgus monkeys were injected with 269 ± 51MBq (7.3 ± 1.4mCi) of [18F]PFBG and 21 whole body PET scans were acquired over 165 min. s around organs to generate time-activity curves. The absorbed doses to individual organs and the effective dose to the whole body were estimated. Favorable distribution of [18F]PFBG was noted with a fast wash-in and wash-out of radioactivity from several tissues. [18F]PFBG rapidly distributed in the heart, liver, kidneys, and adrenal glands. The uptake presented as %ID in the brain, lung, and spleen was 1.06 ± 0.45, 6.28 ± 0.33, and 1.39 ± 0.35 at 1min and decreased to 0.29 ± 0.02, 1.78 ± 0.31, and 0.66 ± 0.22 by 112min. In general, a two- to fourfold reduction was noted from peak radioactivity levels. Rapid uptake and significant retention of radioactivity was noted in the heart and the septal wall was distinctly visible by 20min. Fast wash-in and washout kinetics for [18F]PFBG resulted in shorter residence times. The residence time for the liver, lungs, kidneys, and spleen were 28.01 ± 7.73min, 2.97 ± 0.56min, 6.04 ± 3.41min, and 1.09 ± 0.33min, respectively. The mean effective dose for the 70-kg male was 0.04 ± 0.00mSv/MBq. The organs receiving the highest radiation dose in the 70-kg male model were the testes (0.11 ± 0.02mGy/MBq), adrenals (0.08 ± 0.01mGy/MBq), and urinary bladder wall (0.08 ± 0.01mGy/MBq). [18F]PFBG shows a favorable biodistribution pattern. Rapid and persistent uptake was noted in innervated organs. Renal clearance was the major path for elimination of [18F]PFBG. The estimated radiation burden from [18F]PFBG was significantly lower than that from [124I]MIBG.

Potential Effect of Prolonged Sevoflurane Anesthesia on the Kinetics of [11C]Raclopride in Non-human Primates

PurposePositron emission tomography (PET) in non-human primates (NHP) is commonly performed under anesthesia, with sevoflurane being a widely used inhaled anesthetic. PET measurement in NHP can be repeated, and a difference in radioligand kinetics has previously been observed between the first and second PET measurement on the same day using sevoflurane anesthesia. In this study, we evaluated the effect of prolonged sevoflurane anesthesia on kinetics and binding potential (BPND) of [11C]raclopride in NHP.ProceduresThree cynomolgus monkeys underwent two to three PET measurements with [11C]raclopride under continuous sevoflurane anesthesia on the same day. The concentration of sevoflurane was adjusted according to the general conditions and safety parameters of the NHP. Time to peak (TTP) radioactivity in the striatum was estimated from time-activity curves (TACs). The BPND in the striatum was calculated by the simplified reference tissue model using the cerebellum as reference region.ResultsIn each NHP, the TTP became shorter in the later PET measurements than in the first one. Across all measurements (n = 8), concentration of sevoflurane correlated with TTP (Spearman’s ρ = − 0.79, p = 0.03), but not with BPND (ρ = − 0.25, p = 0.55).ConclusionsThese data suggest that sevoflurane affects the shape of TACs but has no evident effect on BPND in consecutive PET measurements.

An open-label, single-dose, phase 1 study of the absorption, metabolism and excretion of quizartinib, a highly selective and potent FLT3 tyrosine kinase inhibitor, in healthy male subjects, for the treatment of acute myeloid leukemia

1. Quizartinib absorption, metabolism and excretion were characterized in six healthy men receiving a single oral dose of 60 mg (≈100 μCi) of [14C]-quizartinib. Blood, plasma, urine and faeces were collected ≤336 h postdose.2. Four hours postdose, maximum mean ± SD blood radioactivity concentrations were 296 ± 67.4 ng equivalents/g. A mean ± SD of 1.64 ± 0.482% and 76.3 ± 6.23% of the dose was recovered in urine and faeces, respectively, within 336 h postdose.3. Radio-detector high-performance liquid chromatography (radio-HPLC) and liquid chromatography–mass spectrometry (LC–MS) showed two main radioactive peaks in plasma, unchanged quizartinib and mono-oxidative metabolite, AC886. Five additional metabolites in plasma were identified by LC–MS, but low levels prevented radio-HPLC detection. Although unchanged quizartinib was the main radioactive component in faeces (mean, 4.0% of administered dose), 15 metabolites representing a mean of 1.0–3.5% of administered dose were found. Quizartinib was predominantly metabolized by phase I biotransformations (oxidation, reduction, dealkylation, deamination, hydrolysis and combinations thereof).4. This study indicated that quizartinib was rapidly and orally bioavailable, extensively metabolized, with AC886 as the major circulating metabolite, and predominantly eliminated in faeces. Quizartinib was well tolerated in the subjects.