Finally, a significantly lower radiochemical yield was observed when DMF was tested as a reaction solvent compared to DMSO (entry 15 vs entry 9, Table 1). In some cases, the presence of N-[ 11C]-4-tolylformamide ([ 11C]3) was detected. This is in agreement with the proposed reaction mechanism in which a N- 11C-formamide would be a pre- cursor for the N- 11C-methyl amine (Additional file 1: Scheme S1). Thus, when DMF was used as a solvent at 100 °C, ([ 11C] 3 ) was obtained with an RCY of 26% (entry 15, Table 1), whereas when using MeCN and DMSO as solvents at 80 and 50 °C, [ 11C] 3 was formed in 8 and 14% of RCY, respectively (entries 1 and 8, Table 1).
AD treatment by means of surgical castration or AR antagonist both affect tumour viability, which can be detected by nuclear imaging techniques. However, in order to compare tracer internalisation in AD-treated versus non-treated animals accurately, tracer metabolism should remain as far as possible unaffected by AD. The biodistribution of [ 18 F]FDG and [ 11C]acetate was studied in control and DES-treated animals . In healthy rats and tumour-bearing mice, AD did not alter tracer clear- ance from the blood. Also, the uptake of both tracers in background tissue compartments such as the liver, muscle and heart was not significantly affected . Therefore, the biodistribution profile of [ 18 F]FDG and [ 11C]acetate is assumed to remain unchanged after AD. This would mean that tracer clearance should not affect PET imaging. Regarding [ 18 F]FDG PET, these data were further confirmed by Jadvar et al. . In a later study of this group, [ 11C]choline biodistribution was studied in castrated and non-treated tumour-bearing mice using autoradiography. The authors concluded that AD did not change clearance of [ 11C]choline . In our present study, we did not observe an altered clearance of [ 18 F] FDG, [ 11C]choline and [ 11C]acetate following castration, which supports these previously obtained results.
Radiolabeled amino acids are well-established tracers for brain tumor imaging with PET. The Response Assess- ment in Neuro-Oncology working group has recently rec- ommended the use of amino acid PET imaging for brain tumor management in addition to magnetic resonance imaging [3, 4]. L-[methyl- 11C]methionine ( 11C-MET) is the most widely used amino acid PET imaging tracer for gliomas for the preoperative detection, diagnosis of sub- types and grades, differential diagnosis from radiation ne- crosis, estimation of tumor infiltration, and delineation of the border of tumor removal [5, 6]. Methyl- 11C-choline, another PET radiotracer, potentially reflects the grade of malignancy . However, the short half-life (20 min) of
We utilized a high-resolution animal PET scanner (SHR- 38000, Hamamatsu Photonics, Japan) under an axial field of view (FOV) of 330 mm, a transaxial FOV of 108 mm, and a transaxial spatial resolution of 2.3 mm in the center. Eight animals were scanned twice a day using PET with [ 11C](R)PK11195 and [ 11C]NE40 beginning 24 h after PIT. The interval between the two scans was set to 2 h, and the order of the scans was counterbalanced. The animals were anesthetized using an initial dose of chloral hydrate (400 mg/kg, i.p.) followed by a continuous infusion of chloral hydrate (100 mg/kg/h, i.v.) during the entire im- aging experiment. They were placed in the prone position on a fixation plate and then set within the gantry hole of the PET scanner. After a 15-min transmission scan utilizing an external 68 Ge/ 68 Ga rod source (67 MBq) for attenuation correction, a serial emission scan that lasted for 60 min was performed immediately following each tracer injection of [ 11C](R)PK11195 or [ 11C]NE40 at a dose of 48 MBq/kg; tracers were injected intravenously through the cannula that was inserted into the tail vein. The specific activity of each tracer used was above 50 GBq/μmol. No arterial sam- pling was conducted. The PET data were reconstructed using 3D DRAMA (iteration 2, gamma 0.1) with a Gauss filter of 1.0 mm in full width at half maximum (FWHM), yielding a voxel size of 0.65 × 0.65 × 1.0167 mm for the re- constructed image. To obtain the anatomical information, X-CT scans were performed immediately following PET measurement using a ClairvivoCT (Shimadzu Corporation, Kyoto, Japan).
of helium and ammonia gases was used. The amount of ammonia used is very critical in obtaining the enantioenrichment in the final product. Racemized product was ob- served if excess ammonia existed at the presence of moisture in the first [ 11C] nitrile in- sertion step, and low yield of [ 11C] CsCN was observed if less ammonia was used. Therefore, the reaction mixture was bubbled with helium to remove excess ammonia. Azeotropic drying of the crown ether and base was performed to remove moisture prior to the reaction. The use of unconventional cesium bicarbonate was due to the re- ported method suggesting [ 11C] CsCN gave the best result (Gleede et al., 2015). The precursor 5 in DMF was added to reaction vessel 1 and heated. After the [ 11C] nitrile insertion step, the resultant [ 11C] nitrile intermediate 6 was purified on a semi-preparative HPLC to remove unreacted [ 11C] CsCN and other potential impur- ities. The intermediate 6 needs to be dried before it is treated with mixture of acids in the second step. Considering the size and geometry of the reaction vessel equipped with the synthesis module, it was observed that using less than 1.5 mL of acetonitrile to elute the intermediate into the second reaction vessel is optimal. Therefore, attempts were made to evaluate the trapping of the intermediate 6 on various solid-phase extrac- tion cartridges with different material and sizes of packing material, such as tC18 vac 3 cc, tC18 light, tC18 plus short, and C18 plus sep-pak. Of the sep-paks used, only the C18 sep-pak plus was able to trap the intermediate 6 efficiently. In order to efficiently elute the intermediate 6 from C18 plus sep-pak, it was observed that at least 1.4 mL of
In order to acquire reliable measurements, a steady state condition in each patient was required. To obtain such a condition, patients fasted prior to the study and refrained from taking amino acid formula. After an overnight fast, some patients consumed a light breakfast with a very lim- ited amount of Phe, whereas other patients remained fasted. We consider the influence of the light breakfast to be minimal, as we previously showed that such a breakfast does neither affect blood Phe nor blood Tyr concentra- tions . Similarly, one could hypothesize that ceasing amino acid formula intake could have affected blood Phe and Tyr concentrations during the study period. First, in- take of amino acid formula could reduce Phe uptake at the gut-blood barrier, thus reducing blood Phe concentra- tions. Second, formula intake could increase blood Tyr concentrations. Whether these effects would in turn influ- ence 11C-Tyr fluxes remains to be investigated.
C reaction by bombarding a mixture of nitro- gen and hydrogen (10%) gas with a beam (35 μA) of pro- tons (16.7 MeV) generated from a biomedical cyclotron (GE PETtrace; Uppsala, Sweden). At the end of irra- diation, the target gas was transferred to a Tracerlab synthesis module (GE PETtrace, Uppsala, Sweden) where the [ 11C]methane was trapped by cooling the gas to − 140 °C. After replacing the target gas with helium, the [ 11C]methane was converted into [ 11C]methyl iodide during 5 min of recirculation of radioactive gas through an iodine evaporation oven at 70 °C, an iodination oven at 720 °C, and a [ 11C]methyl iodide trap. The [ 11C]me- thyl iodide was released by heating the trap to 190 °C and then passed through a heated column of AgOTf to generate [ 11C]methyl triflate. The [ 11C]methyl triflate was transferred to a septum-sealed reaction vessel (5 mL) containing N-desmethyl precursor (0.1–0.5 mg) and NaOH (0.5 M, 6 μL) in acetone (400 μL). After 2 min at ambient temperature, the reaction mixture was diluted with water (3 mL) and injected onto a reversed phased ACE C-18 HPLC column (250 × 10 mm; Advanced Chromatography Technologies Ltd.; Aberdeen, UK) using a mobile phase of 60% aqueous HCO 2 NH 4 (0.1 M)
Approximately 30% of FNH lesions showed increased uptake of [ 11C]ACE, and it was not possible to discrim- inate FNH from HCC based on visual assessment or differences in semi-quantitative analysis. The results of the present study indicate that both tracers detect a vari- able yet low percentage of lesions representing HCC and FNH. No liver metastases of other primary tumors were detected with these tracers. However, due to the limited cases and limited kinds of cancers, i.e., only six liver me- tastases and four metastases of colon cancer, this might not be conclusive. The fact that liver metastases of colo- rectal cancer do not take up lipid PET tracers has already been published . In contrast, should this group be larger, uptake would be expected in metastases from prostate cancers and some others (lung, breast).
the radiolabeled form of the glucuronide conjugate (M2), leaving only the M1 fraction . Caspar et al.  found that the O -demethylation is catalyzed by CYP2C19 (cytochrome P-450 enzyme) and CYP2D6, and the relative contribution to hepatic clearance was estimated to be 69% for CYP2D6, with the remaining clearance attributed to CYP2C19 and CYP3A4 (catalyz- ing N -dealkylation and/or hydroxylation). These CYP isoforms are also found in the small intestines , which we hypothesize account for part of the high up- take of 11C-Cimbi-36 in the proximal small intestine throughout the scan. The other part possibly represent- ing specific binding to 5-HT 2A/2C Rs. 11C-Cimbi-36 also
mation is not only relevant when the radiopharmaceuti- cals are used to evaluate actions of novel drugs which may show biased agonism but also because β-arrestin-2 itself may be involved in the desensitization of DA re- ceptors and as such in the detection of DA. Literature about biased signalling of currently available agonist PET radiotracers 11C-NPA and 11C-PHNO at cloned DA receptors does not exist, and therefore, we tested un- labelled (‘cold’) NPA and PHNO for agonism in both the cAMP and β-arrestin-2 assays.
also express CB2 reduces detectable radioactivity. Re- cently, we reported that [ 11C]NE40 binding is increased in the peri-infarct area of the ipsilateral cortex at 24 h after induction of stroke, but not in the contralateral cortex, using a photothrombotic stroke model . Fol- lowing CB2 activation, uptake of a TSPO tracer is ob- served at the chronic stage, indicating that different inflammatory responses of microglia occur in the acute and chronic states after ischemia . This early activa- tion of CB2 might also be observed in a variety of animal models of neurological disorders such as AD, multiple sclerosis, and amyotrophic lateral sclerosis . How- ever, it is unclear whether CB2 is upregulated in animal models of senescence or early-stage mild cognitive impairment.
Unlike boronic acids, organotrifluoroborates are stable in crystalline solid form and in aprotic solutions making them attractive as precursor materials for synthesis of PET- tracers (Lennox and Lloyd-Jones 2014). However, as already mentioned trifluoroborates need to be converted to boronic acid derivatives in aqueous or protic media to be acti- vated for transmetalation reactions (Lennox and Lloyd-Jones 2014). While conventional catalysis reactions with organotrifluoroborates can proceed for hours, the short half-life of carbon-11 necessitate very short reaction time of a few minutes and rapid initial for- mation of boronic acid is therefore needed. Boronic acid derivatives have also been used directly as precursors in Suzuki-Miyaura reactions, for example in the synthesis of [ 11C]M-MTEB (Hamill et al. 2005). However, boronic acids can undergo side reactions under coupling conditions, e.g. oxidation, protodeboronation and palladium catalyzed homocoupling. By hydrolyzing trifluoroborates in situ to form moderate concentrations of active species, the reaction can be directed towards the Suzuki-Miyaura coupling re- action more selectively (Lennox and Lloyd-Jones 2014). The hydrolysis rate of trifluoro- borates can be controlled in biphasic solvent system that has slightly basic organic phase and very basic aqueous phase. (Lennox and Lloyd-Jones 2014) Besides DMF- water solvent systems, hydrolysis can also occur in more homogenous solvent mixtures such as THF and water in a 10:1 ratio in the presence of a carbonate salt (Lennox and Lloyd-Jones 2014). THF has also shown to be an excellent solvent for other types of transition metal mediated 11C-labelling reactions, e.g. carbonylations (Eriksson et al. 2012; Takashima-Hirano et al. 2012; Roslin et al. 2017; Schembri et al. 2019) and Heck reactions (Wang et al. 2015).
Improved resistance to MAO-A will potentially yield markedly increased intracellular retention of [ 11C]HTP in neuroendocrine tissues. [ 11C]HTP is currently used as a universal diagnostic imaging biomarker for benign and malignant NETs . However, a higher amount of intact [ 11C]HTP in plasma has been shown to improve the tracer uptake in NETs, and patients therefore are pre- medicated with the AADC inhibitor 100 to 200 mg car- bidopa orally 1 h prior to the PET examination . This procedure not only improves sensitivity but also intro- duces a new parameter that directly influences absolute uptake in lesions: the individual time for gastrointestinal absorption of carbiodopa. Additionally, the time from in- gestion of carbidopa until PET examination can be vari- able in case of delays in radiochemistry. This taken together makes direct quantitative comparison between examinations - even repeated scans within an individual - impossible or difficult. Importantly, it precludes the possibility of quantitatively monitoring treatment effi- cacy by using SUVs in individual lesions.
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The forum and method of these discussions is just as significant as the requirement for openness. The debates over ACTA and SOPA (and, in a more peripheral way, Bill C-11) show that both governments and copyright holders need to improve their methods of disseminating information. Opponents of ACTA and SOPA were able to reach wide audiences quickly and, most significantly, to mobilize them quickly. Regardless of the merits of their viewpoints, the opponents have arguably the most important factor weighing heavily in their favor: they know how to communicate their message, and they know how to do so persuasively. Opponents (particularly the technology industry) have and will maintain a head start on the government in communication; they control powerful means of dissemination in that they run the major websites. This should encourage copyright holders and the government to talk more directly with them in order to prevent drastic measures like the anti-SOPA blackout.
method of Camsonne et al . Briefly, 1 mg of the pre- cursor (N-sec-butyl-1-(2-chlorophenyl) isoquinoline-3- carboxamide) was dissolved in 500 µL DMSO with 5–10 mg KOH, after trapping the C-11 methyl iodide, the vessel was heated at 80°C for 3 min and purified by HPLC sys- tem comprising a mobile phase pump (Hitachi), an auto- matic sample injector with 5 ml loop (Merck) and a radioactivity detector (in-house construction). Separation was performed on a µ-Bondapak C-18 column (7.8–300 mm, Waters) using methanol and 0.01 M phosphoric acid (700 / 300, v/v) as the mobile phase with a flow of 8 ml/ min. The radioactivity peak with a retention time of 5.6 min, similar to a reference standard was collected. After addition of 50 µL 5 M HCl, the collected fraction was evaporated and the residue was dissolved in saline buffer and sterilized by filtration through a 0.2-µm filter (Millex ® -GV). About 50% of the radioactivity was trapped