Automated sulfur-[18F]fluoride exchange radiolabelling of a prostate specific membrane antigen (PSMA) targeted ligand using the GE FASTlabTM cassette-based platform† † Electronic supplementary information (ESI) available: Chemical synthesis and characterisation, biological evaluation in vitro and in vivo. See DOI: https://doi.org/10.1039/d3re00307h
Ontology highlight
ABSTRACT:
SUBMITTER: Yang Z
PROVIDER: S-EPMC10520611 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The use of biologics in positron emission tomography (PET) imaging is an important area of radiopharmaceutical development and new automated methods are required to facilitate their production. We report an automated radiosynthesis method to produce a radiolabelled biologic via facile inverse electron demand Diels-Alder (IEDDA) "click" chemistry on a single GE FASTLab™ cassette. We exemplified the method by producing a fluorine-18 radiolabelled interleukin-2 (IL2) radioconjugate from a trans-cyclooctene (TCO) modified IL2 precursor. The radioconjugate was produced using a fully automated radiosynthesis on a single FASTLab™ cassette in a decay-corrected radiochemical yield (RCY, d.c.) of 19.8 ± 2.6% in 110 min (from start of synthesis); the molar activity was 132.3 ± 14.6 GBq μmol-1. The in vitro uptake of [18F]TTCO-IL2 correlated with the differential receptor expression (CD25, CD122, CD132) in PC3, NK-92 and activated human PBMCs. The automated method may be adapted for the radiosynthesis of any TCO-modified protein via IEDDA chemistry.
| S-EPMC8167423 | biostudies-literature
Project description:The lack of efficient [18F]fluorination processes and target-specific organofluorine chemotypes remains the major challenge of fluorine-18 positron emission tomography (PET). We report here an ultrafast isotopic exchange method for the radiosynthesis of novel PET agent aryl [18F]fluorosulfate enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully automated 18F-radiolabeling of 25 structurally and functionally diverse aryl fluorosulfates with excellent radiochemical yield (83-100%, median 98%) and high molar activity (280 GBq μmol-1) at room temperature in 30 s. The purification of radiotracers requires no time-consuming HPLC but rather a simple cartridge filtration. We further demonstrate the imaging application of a rationally designed poly(ADP-ribose) polymerase 1 (PARP1)-targeting aryl [18F]fluorosulfate by probing subcutaneous tumors in vivo.
| S-EPMC8418205 | biostudies-literature
Project description:Early detection and treatment of cancers can significantly increase patient prognosis and enhance the quality of life of affected patients. The emerging significance of the tumor microenvironment (TME) as a new frontier for cancer diagnosis and therapy may be exploited by radiolabeled tracers for diagnostic imaging techniques such as positron emission tomography (PET). Cancer-associated fibroblasts (CAFs) within the TME are identified by biomarkers such as fibroblast activation protein alpha (FAPα), which are expressed on their surfaces. Targeting FAPα using small-molecule 18F-labeled inhibitors (FAPIs) has recently garnered significant attention for non-invasive tumor visualization using PET. Herein, two potent aryl-fluorosulfate-based FAPIs, 12 and 13, were synthetically prepared, and their inhibition potency was determined using a fluorimetric FAP assay to be IC50 9.63 and 4.17 nM, respectively. Radiofluorination was performed via the sulfur [18F]fluoride exchange ([18F]SuFEx) reaction to furnish [18F]12 and [18F]13 in high activity yields (AY) of 39-56% and molar activities (Am) between 20-55 GBq/µmol. In vitro experiments focused on the stability of the radiolabeled FAPIs after incubation with human serum, liver microsomes and liver cytosol. Preliminary PET studies of the radioligands were performed in healthy mice to investigate the in vivo biodistribution and 18F defluorination rate. Fast pharmacokinetics for the FAP-targeting tracers were retained and considerable bone uptake, caused by either 18F defluorination or radioligand accumulation, was observed. In summary, our findings demonstrate the efficiency of [18F]SuFEx as a radiolabeling method as well as its advantages and limitations with respect to PET tracer development.
| S-EPMC10747913 | biostudies-literature
Project description:[18F]Gln-OSO2F, [18F]Arg-OSO2F, and [18F]FSY-OSO2F were designed by introducing sulfonyl 18F-fluoride onto glutamine, arginine, and tyrosine, respectively. [18F]FSY-OSO2F can be prepared directly by sulfur 18F-fluoride exchange, while [18F]Gln-OSO2F and [18F]Arg-OSO2F require a two-step labeling method. Those tracers retain their typical transport characteristics for unmodified amino acids. Both PET imaging and biodistribution confirmed that [18F]FSY-OSO2F visualized MCF-7 and 22Rv1 subcutaneous tumors with high contrast, and its tumor-to-muscle ratio was better than that of [18F]FET. However, [18F]Gln-OSO2F and [18F]Arg-OSO2F poorly image MCF-7 subcutaneous tumors, possibly due to differences in the types and amounts of transporters expressed in tumors. All three tracers can visualize the U87MG glioma. According to our biological evaluation, none of the tracers evaluated in this study exhibited obvious defluorination, and subtle structural changes led to different imaging characteristics, indicating that the application of sulfur 18F-fluoride exchange click chemistry in the design of radioactive sulfonyl fluoride amino acids is feasible and offers significant advantages.
| S-EPMC10860173 | biostudies-literature
Project description:The reaction between ribonucleosides and ex situ generated sulfonyl fluoride has been developed. The reaction takes place at the -NH2 groups of nucleobases, and the resulting nucleosides are equipped with a sulfamoyl fluoride moiety, dubbed SuFNucs. These species undergo a selective sulfur fluoride exchange (SuFEx) reaction with various amines, leading to sulfamide-functionalized derivatives of adenosine, guanosine, and cytidine (SulfamNucs). The scope and examples of further SuFNucs fuctionalization leading to nucleotides, oligonucleotides, and peptide-nucleoside conjugates are presented.
| S-EPMC9295159 | biostudies-literature
Project description:Positron emission tomography (PET) is an in vivo imaging technology that utilizes positron-emitting radioisotope-labeled compounds as PET radiotracers that are commonly used in clinic and in various research areas, including oncology, cardiology, and neurology. Fluorine-18 is the most widely used PET-radionuclide and commonly produced by proton bombardment of 18O-enriched water in a cyclotron. The [18F]fluoride thus obtained generally requires processing by azeotropic drying in order to completely remove H2O before it can be used for nucleophilic radiofluorination. In general, the drying step is important in facilitating the radiofluorination reactions and the preparation of 18F-labeled PET radiotracers. In this communication, we have demonstrated the feasibility of using [18F]tosyl fluoride ([18F]TsF) as a versatile [18F]fluoride source for radiofluorination to bypass the azeotropic drying step, and we have developed a continuous flow solid-phase radiosynthesis strategy to generate [18F]TsF in a form that is excellent for radiofluorination. [18F]TsF shows high reactivity in radiofluorination and provides the features suitable for preparing PET radiotracers on a small scale and exploring novel radiolabeling technologies. Thus, using [18F]TsF as a [18F]fluoride source is a promising strategy that facilitates radiofluorination and provides a convenient and efficient solution for the preparation of 18F-labeled radiopharmaceuticals that is well matched to the emerging trends in PET imaging technologies.
| S-EPMC9950486 | biostudies-literature
Project description:Optimization of small-molecule probes or drugs is a synthetically lengthy, challenging, and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible sulfur(VI) fluoride exchange (SuFEx) click chemistry. A high-throughput screening hit benzyl (cyanomethyl)carbamate (Ki = 8 ?M) against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RN?S(O)F2] motif, rapidly diversified into 460 analogs in overnight reactions, and the products were directly screened to yield drug-like inhibitors with 480-fold higher potency (Ki = 18 nM). We showed that the improved molecule is active in a bacteria-host coculture. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates.
| S-EPMC7751259 | biostudies-literature
Project description:BackgroundRoutine prostate-specific membrane antigen (PSMA) positron emission tomography (PET) performed for primary staging or restaging of prostate cancer patients is usually done as a single static image acquisition 60 min after tracer administration. In this study, we employ dynamic whole-body (D-WB) PET imaging to compare the pharmacokinetics of [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 in various tissues and lesions, and to assess whether Patlak parametric images are quantitative and improve lesion detection and image readability.MethodsTwenty male patients with prostate cancer were examined using a D-WB PSMA PET protocol. Ten patients were scanned with [68Ga]Ga-PSMA-11 and ten with [18F]PSMA-1007. Kinetic analyses were made using time-activity curves (TACs) extracted from organs (liver, spleen, bone, and muscle) and lesions. For each patient, three images were produced: SUV + Patlak parametric images (Ki and DV). All images were reviewed visually to compare lesion detection, image readability was quantified using target-to-background ratios (TBR), and Ki and DV values were compared.ResultsThe two PSMA tracers exhibited markedly different pharmacokinetics in organs: reversible for [68Ga]Ga-PSMA-11 and irreversible for [18F]PSMA-1007. For both tracers, lesions kinetics were best described by an irreversible model. All parametric images were of good visual quality using both radiotracers. In general, Ki images were characterized by reduced vascular signal and increased lesion TBR compared with SUV images. No additional malignant lesions were identified on the parametric images.ConclusionD-WB PET/CT is feasible for both PSMA tracers allowing for direct reconstruction of parametric Ki images. The use of multiparametric PSMA images increased TBR but did not lead to the detection of more lesions. For quantitative whole-body Ki imaging, [18F]PSMA-1007 should be preferred over [68Ga]Ga-PSMA-11 due to its irreversible kinetics in organs and lesions.
| S-EPMC10105814 | biostudies-literature
Project description:PurposeProstate-Specific Membrane Antigen (PSMA) PET/CT has been introduced as a sensitive method for characterizing metastatic prostate cancer. The purpose of this study is to compare the spatial concordance of 18F-NaF PET/CT and 18F-PSMA-targeted PET/CT within prostate cancer bone metastases.MethodsProstate cancer patients with known bone metastases underwent PSMA-targeted PET/CT (18F-DCFBC or 18F-DCFPyL) and 18F-NaF PET/CT. In pelvic and spinal lesions detected by both radiotracers, regions-of-interest (ROIs) derived by various thresholds of uptake intensity were compared for spatial colocalization. Overlap volume was correlated with uptake characteristics and disease status.ResultsThe study included 149 lesions in 19 patients. Qualitatively, lesions exhibited a heterogeneous range of spatial concordance between PSMA and NaF uptake from completely matched to completely discordant. Quantitatively, overlap volume decreased as a function of tracer intensity. and disease status, where lesions from patients with castration-sensitive disease showed higher spatial concordance while lesions from patients with castration-resistant disease demonstrated more frequent spatial discordance.ConclusionAs metastatic prostate cancer progresses from castration-sensitive to castration-resistant, greater discordance is observed between NaF PET and PSMA PET uptake. This may indicate a possible phenotypic shift to tumor growth that is more independent of bone remodeling via osteoblastic formation.
| S-EPMC6340866 | biostudies-literature
Project description:The proximity-enabled sulfur(vi) fluoride exchange (SuFEx) reaction generates specific covalent linkages between proteins in cells and in vivo, which opens innovative avenues for studying elusive protein-protein interactions and developing potent covalent protein drugs. To exploit the power and expand the applications of covalent proteins, covalent linkage formation between proteins is the critical step, for which fundamental kinetic and essential properties remain unexplored. Herein, we systematically studied SuFEx kinetics in different proteins and conditions. In contrast to in small molecules, SuFEx in interacting proteins conformed with a two-step mechanism involving noncovalent binding, followed by covalent bond formation, exhibiting nonlinear rate dependence on protein concentration. The protein SuFEx rate consistently changed with protein binding affinity as well as chemical reactivity of the functional group and was impacted by target residue identity and solution pH. In addition, kinetic analyses of nanobody SR4 binding with SARS-CoV-2 spike protein revealed that viral target mutations did not abolish covalent binding but decreased the SuFEx rate with affinity decrease. Moreover, off-target cross-linking of a SuFEx-capable nanobody in human serum was not detected, and the SuFEx-generated protein linkage was stable at cellular acidic pHs, suggesting SuFEx suitability for in vivo usage. These results advanced our understanding of SuFEx reactivity and kinetics in proteins, which is invaluable for ongoing exploration of SuFEx-enabled covalent proteins for basic biological research and creative biotherapeutics.
| S-EPMC10370592 | biostudies-literature