Late-Stage 18 F-Difluoromethyl Labeling of N-Heteroaromatics with High Molar Activity for PET Imaging.
Ontology highlight
ABSTRACT:
SUBMITTER: Trump L
PROVIDER: S-EPMC6790700 | biostudies-literature | 2019 Sep
REPOSITORIES: biostudies-literature
Publications
Late-Stage <sup>18</sup> F-Difluoromethyl Labeling of N-Heteroaromatics with High Molar Activity for PET Imaging.
Trump Laura L Lemos Agostinho A Lallemand Bénédicte B Pasau Patrick P Mercier Joël J Lemaire Christian C Luxen André A Genicot Christophe C
Angewandte Chemie (International ed. in English) 20190809 37
Despite a growing interest in CHF<sub>2</sub> in medicinal chemistry, there is a lack of efficient methods for the insertion of CHF<sup>18</sup> F into druglike compounds. Herein described is a photoredox flow reaction for <sup>18</sup> F-difluoromethylation of N-heteroaromatics that are widely used in medicinal chemistry. Following the two-step synthesis for a new <sup>18</sup> F-difluoromethylation reagent, the photoredox reaction is completed within two minutes and proceeds by C-H activation, ...[more]
Similar Datasets
Project description:Pretargeted imaging can be used to visualize and quantify slow-accumulating targeting vectors with short-lived radionuclides such as fluorine-18 - the most popular clinically applied Positron Emission Tomography (PET) radionuclide. Pretargeting results in higher target-to-background ratios compared to conventional imaging approaches using long-lived radionuclides. Currently, the tetrazine ligation is the most popular bioorthogonal reaction for pretargeted imaging, but a direct 18F-labeling strategy for highly reactive tetrazines, which would be highly beneficial if not essential for clinical translation, has thus far not been reported. In this work, a simple, scalable and reliable direct 18F-labeling procedure has been developed. We initially studied the applicability of different leaving groups and labeling methods to develop this procedure. The copper-mediated 18F-labeling exploiting stannane precursors showed the most promising results. This approach was then successfully applied to a set of tetrazines, including highly reactive H-tetrazines, suitable for pretargeted PET imaging. The labeling succeeded in radiochemical yields (RCYs) of up to approx. 25%. The new procedure was then applied to develop a pretargeting tetrazine-based imaging agent. The tracer was synthesized in a satisfactory RCY of ca. 10%, with a molar activity of 134 ± 22 GBq μmol-1 and a radiochemical purity of >99%. Further evaluation showed that the tracer displayed favorable characteristics (target-to-background ratios and clearance) that may qualify it for future clinical translation.
| S-EPMC8442695 | biostudies-literature
Project description:PurposeThe aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection.MethodsTwenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI.Results18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5?±?2.3), while 11C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0?±?2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p?<?0.0001). This was due to 18F-Fluciclovine's lower background in normal brain tissue (0.5?±?0.2 compared to 1.3?±?0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7?±?2.3 h), and achieving a consistent final distribution volume averaging 1.4?±?0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57?±?51 min), with an average distribution volume of 3.2?±?1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine.ConclusionTumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.
| S-EPMC7188736 | biostudies-literature
Project description:A simple and rapid method for 18 F radiolabelling of [GaF3 (BnMe2 -tacn)] by 18 F/19 F isotopic exchange is described. The use of MeCN/H2 O or EtOH/H2 O (75:25) and aqueous [18 F]F- (up to 200 MBq) with heating (80 °C, 10 min) gave 66±4 % 18 F incorporation at a concentration of 268 nm, and 37±5 % 18 F incorporation at even lower concentration (27 nm), without the need for a Lewis acid promoter. A solid-phase extraction method was established to give [Ga18 F19 F2 (BnMe2 -tacn)] in 99 % radiochemical purity in an EtOH/H2 O mixture.
| S-EPMC6055623 | biostudies-literature
Project description:Poly(ADP-ribose) polymerase (PARP) inhibitors are increasingly being studied as cancer drugs, as single agents, or as a part of combination therapies. Imaging of PARP using a radiolabeled inhibitor has been proposed for patient selection, outcome prediction, dose optimization, genotoxic therapy evaluation, and target engagement imaging of novel PARP-targeting agents. Methods: Here, via the copper-mediated 18F-radiofluorination of aryl boronic esters, we accessed, for the first time (to our knowledge), the 18F-radiolabeled isotopolog of the Food and Drug Administration-approved PARP inhibitor olaparib. The use of the 18F-labeled equivalent of olaparib allows direct prediction of the distribution of olaparib, given its exact structural likeness to the native, nonradiolabeled drug. Results: 18F-olaparib was taken up selectively in vitro in PARP-1-expressing cells. Irradiation increased PARP-1 expression and 18F-olaparib uptake in a radiation-dose-dependent fashion. PET imaging in mice showed specific uptake of 18F-olaparib in tumors expressing PARP-1 (3.2% ± 0.36% of the injected dose per gram of tissue in PSN-1 xenografts), correlating linearly with PARP-1 expression. Two hours after irradiation of the tumor (10 Gy), uptake of 18F-olaparib increased by 70% (P = 0.025). Conclusion: Taken together, we show that 18F-olaparib has great potential for noninvasive tumor imaging and monitoring of radiation damage.
| S-EPMC6448459 | biostudies-literature
Project description:BackgroundThe clinical diagnosis of deep sternal wound infection (DSWI) is supported by imaging findings including 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT). To avoid misinterpretation due to normal post-surgery inflammation we assessed normal imaging findings in non-infected patients after sternotomy.MethodsThis is a prospective cohort study including non-infectious patients with sternotomy. All patients underwent 18F-FDG-PET/CT at either 5 weeks (group 1), 12 weeks (group 2) or 52 weeks (group 3) post-surgery. 18F-FDG uptake was scored visually in five categories and assessed quantitatively.ResultsA total of 44 patients were included. Sternal mean SUVmax was 7.34 (± 1.86), 5.22 (± 2.55) and 3.20 (± 1.80) in group 1, 2 and 3, respectively (p < 0.01). Sternal mean SUVmean was 3.84 (± 1.00), 2.69 (± 1.32) and 1.71 (± 0.98) in group 1, 2 and 3 (p < 0.01). All patients in group 1 had elevated uptake whereas group 2 and 3 showed 2/15 (13%) and 11/20 (55%) patients respectively with no elevated uptake. Group 3 still showed an elevated uptake pattern in in 9/20 (45%) and in 3/9 (33%) with a high-grade diffuse uptake pattern.ConclusionThis study shows significant lower sternal 18F-FDG at 55 weeks compared to 5 weeks post-sternotomy however elevated uptake patterns may persist.
| S-EPMC10261398 | biostudies-literature
Project description:The last 2-3 years have seen numerous relationships develop between organometallic chemists, fluorine chemists and PET Centers around the world. These collaborations have led to the development of many new strategies for the late-stage introduction of fluorine-18 into complex bioactive molecules. In this perspective we highlight recent developments and key milestones since 2011.
| S-EPMC4217215 | biostudies-literature
Project description:Neurodegenerative biomarkers support diagnosis and measurement of disease progression in the Alzheimer's disease (AD) continuum. 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG-PET), which measures glucose metabolism, is one of the most commonly used biomarkers of neurodegeneration, but is expensive and requires exposure to ionizing radiation. Arterial Spin Labeled (ASL) perfusion Magnetic Resonance Imaging (MRI) provides non invasive quantification of cerebral blood flow (CBF), which is believed to be tightly coupled to glucose metabolism. Here we aimed to compare the performances of ASL derived CBF and 18F-FDG-PET derived standardized uptake value ratio (SUVR) in discriminating patients with mild cognitive impairment (MCI) from older Controls. 2D pseudo continuous ASL and 18F-FDG-PET data with adequate scan quality from 50 MCI study participants (age=73.0 ± 7.0 years, 16 female) and 35 older controls (age=70.2 ± 6.9 years, 20 female), acquired in close temporal proximity, usually on the same day, were considered for this study. We assessed Control-patient group differences both at voxel level and within a priori regions of interest (ROIs). We also compared their area under receiver operating characteristic curves (AUC) with mean CBF or SUVR in a priori selected posterior cingulate cortex (PCC). CBF and 18F-FDG-PET showed abnormalities in similar areas, particularly in medial temporoparietal regions, consistent with the typically observed pattern of prodromal AD. The hypoperfusion pattern with relative CBF (obtained by normalizing voxel CBF values with mean CBF in putamen) was more localized than with absolute CBF. Pearson's correlation coefficients between the T-scores corresponding to the group-differences obtained with 18F-FDG-PET SUVR and absolute and relative ASL CBF were 0.46 and 0.43 (p<0.001), respectively. ROI analyses were also consistent, with the strongest differences observed in PCC (p<0.01). 18F-FDG-PET SUVR, absolute and relative CBF in the PCC ROI demonstrated moderate and similar discriminatory power in predicting MCI status with AUC of 0.71 ± 0.12, 0.77 ± 0.12 and 0.74 ± 0.13, respectively. In conclusion, ASL CBF may be a reasonable, less expensive and safer substitute for 18F-FDG-PET in clinical research.
| S-EPMC6957781 | biostudies-literature
Project description:The effect on survival of radiographic lymph node metastasis in uterine cervical cancer patients is more important than before, even though its prognostic value not been well investigated. The aim of our study is to evaluate the prognostic potential of 18F-fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) compared with Computed Tomography (CT) in uterine cervical cancer patients with stage IIICr allocated by imaging. Fifty-five patients with biopsy-proven primary cervical cancer underwent definitive radiation therapy for stages IIB-IVB of The International Federation of Gynecology and Obstetrics (FIGO) 2018 classifications. The prognostic performance of pretreatment 18F-FDG PET and CT for assessing lymph node metastasis was evaluated by two experienced readers. The PET and CT findings were correlated with the risk of progression-free survival (PFS) and overall survival (OS). Kaplan-Meier survival curves showed that PFS was significantly worse in patients with positive lymph nodes on 18F-FDG PET than in those patients with negative lymph nodes on 18F-FDG PET (p = 0.003), whereas there was no significant difference in PFS between patients with lymph nodes sized ≥ 1 cm and those sized < 1 cm (p = 0.140). Univariate analysis showed that positive lymph nodes on 18F-FDG PET was significantly associated with poor PFS (p = 0.006), whereas lymph node size was not significantly associated with poor PFS (p = 0.145). In multivariate analysis, positive lymph nodes on 18F-FDG PET was significantly associated with poor PFS (p = 0.006) and was an independent prognostic factor for PFS. 18F-FDG PET offers high prognostic value for patients with stage IIICr allocated by imaging compared with CT, suggesting that 18F-FDG PET might be useful in clinical staging decisions and thus promote optimal diagnostic and therapeutic strategies.
| S-EPMC10620427 | biostudies-literature
Project description:BACKGROUND:The folate receptor (FR) is a well-established target for tumor imaging and therapy. To date, only a few 18?F-folate conjugates via 18?F-prosthetic group labeling for positron emission tomography (PET) imaging have been developed. To some extent, they all lack the optimal balance between efficient radiochemistry and favorable in vivo characteristics. METHODS:A new clickable olate precursor was synthesized by regioselective coupling of folic acid to 11-azido-3,6,9-trioxaundecan-1-amine at the ?-position of the glutamic acid residue. The non-radioactive reference compound was synthesized via copper-catalyzed azide-alkyne cycloaddition of 3-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)prop-1-yne and ?-(11-azido-3,6,9-trioxaundecanyl)folic acid amide. The radiosynthesis was accomplished in two steps: at first a 18?F-fluorination of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl-4-methylbenzenesulfonate, followed by a 18?F-click reaction with the ?-azido folate. The in vitro, ex vivo, and in vivo behaviors of the new 18?F-folate were investigated using FR-positive human KB cells in displacement assays and microPET studies using KB tumor-bearing mice. RESULTS:The new 18?F-folate with oligoethylene spacers showed reduced lipophilicity in respect to the previously developed 18?F-click folate with alkyl spacers and excellent affinity (Ki?=?1.6 nM) to the FR. Combining the highly efficient 18?F-click chemistry and a polar oligoethylene-based 18?F-prosthetic group facilitated these results. The overall radiochemical yield of the isolated and formulated product averages 8.7%. In vivo PET imaging in KB tumor-bearing mice showed a tumor uptake of 3.4% ID/g tissue, which could be reduced by FR blockade with native folic acid. Although the new 18?F-oligoethyleneglycole (OEG)-folate showed reduced hepatobiliary excretion over time, a distinct unspecific abdominal background was still observed. CONCLUSIONS:A new 18?F-folate was developed, being available in very high radiochemical yields via a fast and convenient two-step radiosynthesis. The new 18?F-OEG-folate showed good in vivo behavior and lines up with several recently evaluated 18?F-labeled folates.
| S-EPMC3849131 | biostudies-literature
Project description:High liver uptake presents a problem for 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) as a radiotracer for imaging cellular proliferation in the liver with positron emission tomography (PET). This investigation re-visited some issues related to the high liver background uptake of [18F]FLT with an animal model of woodchucks. Several enzymes involved in the hepatic catabolism of FLT, thymidine phosphorylase (TP, TYMP), uridine 5'-diphospho-glucuronosyl-transferases (UDP-GTs, short for UGTs), and β-glucuronidase (GUSB), their homology as well as hepatic expression between the human and the woodchuck was examined. Inhibitors of these enzymes, TP inhibitor (TPI) tipiracil hydrochloride, UGT inhibitor probenecid, β-glucuronidase inhibitor L-aspartate, were administered to the animals at human equivalent doses either intravenously (i.v.) and orally before the injection of tracer-dose [18F]FLT for PET imaging to examine any changes in liver uptake. Liver tissue samples were harvested from the animals after PET imaging and used to perform polymerase chain reaction (PCR) for TP expression or assays for enzymatic activities of TP and β-glucuronidase. Non-radiolabeled (cold) FLT was also applied for enzyme saturation. Animals administered with TPI displayed lower radioactivity in the liver in comparison with the baseline scan. The application of probenecid did not change [18F]FLT liver uptake even though it reduced renal uptake. L-aspartate reduced the liver background uptake of [18F]FLT slightly. The application of cold FLT reduced overall uptake of [18F]FLT including the liver background. Therefore, the combined application of cold FLT and [18F]FLT merits further clinical investigation for reducing liver background uptake of [18F]FLT.
| S-EPMC7675117 | biostudies-literature