Search Results (121)

Background/Objectives: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are highly sensitive clinical imaging modalities, frequently employed in conjunction with magnetic resonance imaging (MRI) or computed tomography (CT) for diagnosing a wide range of disorders. Efficient and robust radiolabeling methods are needed to accommodate the increasing demand for PET and SPECT tracer development. Copper-mediated radiohalogenation (CMRH) reactions enable rapid late-stage preparation of radiolabeled arenes, yet synthetic challenges and radiolabeling precursors’ instability can limit the applications of CMRH approaches. Methods: A series of aryl-boronic acids were converted into their corresponding aryl-boronic acid 1,1,2,2-tetraethylethylene glycol esters [ArB(Epin)s] and aryl-boronic acid 1,1,2,2-tetrapropylethylene glycol esters [ArB(Ppin)s] as stable and versatile precursor building blocks for radiolabeling via CMRH. General protocols for the preparation of ¹⁸F-labeled and ¹²³I-labeled arenes utilizing CMRH of these substrates were developed and applied. The radiochemical conversions (RCC) were determined by radio-(U)HPLC. Results: Both ArB(Epin)s and ArB(Ppin)s-based radiolabeling precursors were prepared in a one-step synthesis with chemical yields of 49–99%. Radiolabeling of the aryl-boronic esters with fluorine-18 or iodine-123 via CMRH furnished the corresponding radiolabeled arenes with RCC of 7–99% and 10–99%, respectively. Notably, a radiohalogenated prosthetic group containing a vinyl sulfone motif was obtained with an activity yield (AY) of 18 ± 3%, and applied towards the preparation of two clinically relevant PET tracers. Conclusions: This approach enables the synthesis of stable radiolabeling precursors and thus provides increased versatility in the application of CMRH, thereby supporting the development of novel PET and SPECT radiotracers. Full article

Background/Objectives: The kinase p38α, a member of the mitogen-activated protein kinase (MAPK) family, is activated by external stimuli and plays a crucial role in inflammation, tumor growth, and metabolic disorders. In particular, p38α is involved in thermogenesis and the metabolism of glucose in brown adipose tissue (BAT), and it contributes to the suppression of obesity and diabetes. The noninvasive imaging of activated p38α could help elucidate diverse pathological processes, including metabolic and inflammatory conditions. This study aimed to develop and evaluate a novel fluorine-18-labeled positron emission tomography (PET) probe for imaging activated p38α in vivo. Methods: We designed 6-(4-[¹⁸F]fluoro-2-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([¹⁸F]R1487) by replacing a fluorine atom in R1487, which is a highly selective p38α inhibitor, with ¹⁸F. A tributylstannyl precursor was reacted with [¹⁸F]KF in the presence of a copper catalyst to synthesize [¹⁸F]R1487. Biodistribution studies and PET/computed tomography (CT) were performed on normal mice to evaluate the in vivo potential of [¹⁸F]R1487. Results: [¹⁸F]R1487 was obtained with a decay-corrected radiochemical conversion of 30.6 ± 5.6% and a decay-corrected radiochemical yield of 6.9 ± 3.6% with a radiochemical purity of >99% after reversed-phase high-performance liquid chromatography purification. The biodistribution study demonstrated high and rapid radioactivity accumulation in BAT (16.3 ± 2.7 %ID/g at 5 min post-injection), with a consistently high BAT-to-blood ratio (>5 over 2 h post-injection). PET/CT imaging successfully visualized BAT with high contrast. Conclusions: These results suggest that [¹⁸F]R1487 is a promising PET probe for imaging activated p38α in vivo, which has potential applications for pathophysiological conditions such as inflammation, cancer, and metabolic disorders. Full article

Even though children’s malignant bone tumours are rare, it is crucial to understand how to identify and stage them accurately to develop an appropriate treatment plan. Ewing’s sarcoma and osteosarcoma are the two main paediatric bone malignancies and require multidisciplinary treatment involving radiologists, orthopaedists, oncologists, pathologists, and paediatricians. These neoplasms may be associated with genetic syndromes but typically occur in patients with no known germline abnormalities. With a frequency of 4.4 per million, osteosarcoma is the most common malignant bone tumour in children. Ewing’s sarcoma has an incidence of 2.5 to 3 per million, making it the second most prevalent. Clinically, these neoplasms present with pain and inflammation in the bones and joints, nocturnal pain unresponsive to drug therapy, systemic symptoms such as fever or weight loss, and persistent symptoms—all of which should prompt clinicians to initiate further diagnostic investigations. The gold standard for diagnosis includes X-ray examination and MRI, which provide an accurate assessment of tumour extension into the medullary canal and surrounding soft tissues. Fluorine-18-labelled FDG-PET scans or fluoro-deoxyglucose positron emission tomography are valuable for evaluating tumour aggressiveness and excluding metastases. A biopsy is mandatory once all other diagnostic tests have been completed. Accurate diagnosis and timely referral to an experienced clinic are essential for ensuring prompt access to treatment and improving patient outcomes. Full article

Fluorinated nucleos(t)ide drugs have proven to be successful chemotherapeutic agents in treating various cancers. The Food and Drug Administration (FDA) has approved several drugs that fit within the fluorinated nucleoside pharmacophore, and many more are either in preclinical development or clinical trials. The addition of fluorine atoms to nucleos(t)ides improves the metabolic stability of the glycosidic bond and, in certain instances, facilitates additional interactions of nucleons(t)ides with receptors. The insertion of fluorine either on sugar or the base of nucleos(t)ides proved to enhance the lipophilicity, pharmacokinetic, and pharmacodynamic properties. Overall, the fluorine atom feeds diverse advantages to the biological profile of nucleos(t)ide analogs by improving their drug-like properties and therapeutic potential. This review article covers the often-used fluorinating reagents in nucleoside chemistry, the clinical significance of [¹⁸F]-labeled nucleosides, the synthesis and anticancer activity of FDA-approved fluoro-nucleos(t)ide drugs, as well as clinical candidates, which are at various stages of clinical development as anticancer agents. Full article

Charge-free gaseous molecules labeled with deuterium ²H (D) atoms elute earlier than their protium-analogs ¹H (H) from most stationary GC phases. This effect is known as the chromatographic H/D isotope effect (hdIE_C) and can be calculated by dividing the retention times (t_R) of the protiated (t_R(H) ) to those of the deuterated (t_R(D)) analytes: hdIE_C = t_R(H)/t_R(D). Analytes labeled with ¹³C, ¹⁵N or ¹⁸O have almost identical retention times and lack a chromatographic isotope effect. Derivatives of cis- and trans-analytes such as cis- and trans-fatty acids also differ in their retention times. Analytes that contain trans-C=C-double bonds elute earlier in gas chromatography-mass spectrometry (GC-MS) than their cis-C=C-double bonds containing congeners. The chromatographic cis/trans-effect (ctE_C) can be calculated by dividing the retention times of the cis- by those of the trans-analytes: ctE_C = t_R(c)/t_R(t). In the present work, the hdIE_C and ctE_C values of endogenous and exogenous substances were calculated from previously reported GC-MS analyses and found to range each between 1.0009 and 1.0400. The examination suggests that the H/D-isotope effects and the cis/trans-effects observed in GC-MS are based on differences in the inter-molecular interaction strengths of the analyte derivatives with the stationary phase of GC columns. The deuterium atoms, being larger than the H atoms of the analytes, attenuate the interaction of the skeleton of the molecules with the GC stationary phase. The angulation of trans-analytes decreases the interaction of the skeleton of the molecules with the GC stationary phase, as only parts of the molecules are close enough to the GC stationary phase to interact. Other chromatographic effects caused by hydrogen (H) and fluorine (F) atoms and by stereo-isomerism are considered to be based on a similar mechanism due to the different orientation of the side chains. Full article

Background: N-succinimidyl-[¹⁸F]fluorobenzoate ([¹⁸F]SFB) is commonly prepared through a three-step procedure starting from [¹⁸F]fluoride ion. A number of methods for the single-step radiosynthesis of [¹⁸F]SFB have been introduced recently, including the radiofluorination of diaryliodonium salts and the Cu-mediated ¹⁸F-fluorination of pinacol aryl boronates and aryl tributyl stannanes, but they still have the drawbacks of lengthy product purification procedures. In the present work, two approaches for the direct labeling of [¹⁸F]SFB from diaryliodonium (DAI) salt (4) and pinacol aryl boronate (6) are evaluated, with a major focus on developing a fast and simple SPE-based purification procedure. Methods: DAI salt precursor 6 was labeled employing the common “minimalist” approach with a two-step reaction heating sequence. The Cu-mediated radiofluorination of 4 was accomplished using Bu₄NOTf as a phase transfer catalyst for the elution of [¹⁸F]fluoride, followed by radiofluorination in the same solvent. Several types of SPE cartridges were tested in the elution and SPE procedures. Results: The Cu-mediated ¹⁸F-fluorination of the pinacol aryl boronate precursor afforded a higher RCC of 56 ± 3% (n = 7), making it better suited for the one-pot synthesis of [¹⁸F]SFB. SPE-based purification was achieved using cation exchange and reverse-phase polymer resin cartridges, connected in series. In a full-batch test, [¹⁸F]SFB was obtained with an RCY of 30% (n. d. c.), RCP > 99%, A_m 96–155 GBq/µmol, and a synthesis time of ≤35 min. Conclusions: Compared to other published methods, [¹⁸F]SFB production via the Cu-mediated radiofluorination of pinacol aryl boronate precursor provides significant time and cost savings, coupled with an ease of implementation. Full article

Introduction: Non-iodine avid metastases of differentiated thyroid cancer (DTC) can be found using PET/CT with a fluorine-18-labeled glucose analog ([¹⁸F]FDG). There are ongoing discussions on the appropriateness of using exogenous thyrotropin (TSH) stimulation before this examination. Material and Methods: In a retrospective study, 73 PET/CT scans with [¹⁸F]FDG performed after exogenous stimulation with recombinant human TSH (rhTSH) and without such stimulation were analyzed. All analyzed patients were suspected of having non-iodine-avid foci of DTC. Results: The stimulation with rhTSH before the PET/CT did not affect the percentage of positive results: 37.5% (18/48) with rhTSH and 40% (10/25) without rhTSH (p = 0.83). The analysis of the ROC curves established the cut-off thyroglobulin point for a positive PET/CT result separately for both subgroups. There was no statistically significant difference between obtaining a positive PET/CT result and the baseline thyroglobulin concentration (both stimulated and unstimulated). The exogenous stimulation of TSH prior to the PET/CT had no effect on the [¹⁸F]FDG uptake in the PET/CT lesions. Conclusions: PET/CT with [¹⁸F]FDG remains a useful method for the diagnosis of non-iodine-avid DTC lesions; in the presented group, a positive effect of rhTSH stimulation on the number of DTC foci visible in the PET/CT was found, but without affecting its effectiveness. Full article

The diagnostic value of imaging Aβ plaques in Alzheimer’s disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [¹⁸F]flotaza, which shows high binding to Aβ plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [¹⁸F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [¹⁸F]flotaza in transgenic 5xFAD mice expressing Aβ plaques. [¹⁸F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aβ and analyzed using QuPath. In vitro and in vivo [¹⁸F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aβ. High [¹⁸F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WM♂/WM♀ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [¹⁸F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [¹⁸F]flotaza exhibited binding to Aβ plaques in 5xFAD mice with SUVR~1.4. [¹⁸F]Flotaza is a new Aβ plaque PET imaging agent that exhibited high binding to Aβ plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [¹⁸F]flotaza to human PET studies may be worthwhile. Full article

The development of conducting polymer incorporated with carbon materials-based electrochemical biosensors has been intensively studied due to their excellent electrical, optical, thermal, physical and chemical properties. In this work, a label-free electrochemical dopamine (DA) biosensor based on polyaniline (PANI) and its aminated derivative, i.e., poly(3-aminobenzylamine) (PABA), composited with functionalized multi-walled carbon nanotubes (f-CNTs), was developed to utilize a conducting polymer as a transducing material. The electrospun nanofibers of the composites were fabricated on the surface of fluorine-doped tin oxide (FTO)-coated glass substrate under the optimized condition. The PANI/f-CNTs and PABA/f-CNTs electrospun nanofibers were characterized by attenuated total reflectance–Fourier transform infrared (ATR-FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM), which confirmed the existence of f-CNTs in the composites. The electroactivity of the electrospun nanofibers was investigated in phosphate buffer saline solution using cyclic voltammetry (CV) before being employed for label-free electrochemical detection of DA using differential pulse voltammetry (DPV). The sensing performances including sensitivity, selectivity, stability, repeatability and reproducibility of the fabricated electrospun nanofiber films were also electrochemically evaluated. The electrochemical DA biosensor based on PANI/f-CNTs and PABA/f-CNTs electrospun nanofibers exhibited a sensitivity of 6.88 µA·cm⁻²·µM⁻¹ and 7.27 µA·cm⁻²·µM⁻¹ in the linear range of 50–500 nM (R² = 0.98) with a limit of detection (LOD) of 0.0974 µM and 0.1554 µM, respectively. The obtained DA biosensor showed great stability, repeatability and reproducibility with precious selectivity under the common interferences, i.e., glucose, ascorbic acid and uric acid. Moreover, the developed electrochemical DA biosensor also showed the good reliability under detection of DA in artificial urine. Full article

Radiolabeled peptides are valuable tools for diagnosis or therapies; they are often radiofluorinated using an indirect approach based on an F-18 prosthetic group. Herein, we are reporting our results on the F-18 radiolabeling of three peptides using two different methods based on click reactions. The first one used the well-known CuAAC reaction, and the second one is based on our recently reported hetero-Diels–Alder (HDA) using a dithioesters (thia-Diels–Alder) reaction. Both methods have been automated, and the ¹⁸F-peptides were obtained in similar yields and synthesis time (37–39% decay corrected yields by both methods in 120–140 min). However, to obtain similar yields, the CuAAC needs a large amount of copper along with many additives, while the HDA is a catalyst and metal-free reaction necessitating only an appropriate ratio of water/ethanol. The HDA can therefore be considered as a minimalist method offering easy access to fluorine-18 labeled peptides and making it a valuable additional tool for the indirect and site-specific labeling of peptides or biomolecules. Full article

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder. Plexiform neurofibromas (PNFs) are benign tumors commonly formed in patients with NF1. PNFs have a high incidence of developing into malignant peripheral nerve sheath tumors (MPNSTs) with a 5-year survival rate of only 30%. Therefore, the accurate diagnosis and differentiation of MPNSTs from benign PNFs are critical to patient management. We studied a fluorine-18 labeled tryptophan positron emission tomography (PET) radiotracer, 1-(2-[¹⁸F]fluoroethyl)-L-tryptophan (L-[¹⁸F]FETrp), to detect NF1-associated tumors in an animal model. An ex vivo biodistribution study of L-[¹⁸F]FETrp showed a similar tracer distribution and kinetics between the wild-type and triple mutant mice with the highest uptake in the pancreas. Bone uptake was stable. Brain uptake was low during the 90-min uptake period. Static PET imaging at 60 min post-injection showed L-[¹⁸F]FETrp had a comparable tumor uptake with [¹⁸F]fluorodeoxyglucose (FDG). However, L-[¹⁸F]FETrp showed a significantly higher tumor-to-brain ratio than FDG (n = 4, p < 0.05). Sixty-minute-long dynamic PET scans using the two radiotracers showed similar kidney, liver, and lung kinetics. A dysregulated tryptophan metabolism in NF1 mice was further confirmed using immunohistostaining. L-[¹⁸F]FETrp is warranted to further investigate differentiating malignant NF1 tumors from benign PNFs. The study may reveal the tryptophan–kynurenine pathway as a therapeutic target for treating NF1. Full article

Background: Magnetic resonance imaging (MRI) is a non-invasive imaging modality which, in conjunction with biopsies, provide a qualitative assessment of tumor response to treatment. Intravenous injection of contrast agents such as fluorine (¹⁹F) nanoemulsions labels systemic macrophages, which can, then, be tracked in real time with MRI. This method can provide quantifiable insights into the behavior of tumor-associated macrophages (TAMs) in the tumor microenvironment and macrophage recruitment during therapy. Methods: Female mice received mammary fat pad injections of murine breast or colon cancer cell lines. The mice then received an intravenous ¹⁹F nanoemulsion injection, followed by a baseline ¹⁹F MRI. For each cancer model, half of the mice then received 8 Gy of localized radiation therapy (RT), while others remained untreated. The mice were monitored for two weeks for tumor growth and ⁹F signal using MRI. Results: Across both cohorts, the RT-treated groups presented significant tumor growth reduction or arrest, contrary to the untreated groups. Similarly, the fluorine signal in treated groups increased significantly as early as four days post therapy. The fluorine signal change correlated to tumor volumes irrespective of time. Conclusion: These results demonstrate the potential of ¹⁹F MRI to non-invasively track macrophages during radiation therapy and its prognostic value with regard to tumor growth. Full article

The polymer/substrate interface plays a significant role in the dynamics of nanoconfined polymers because of its suppression on polymer mobility and its long-range propagation feature, while the molecular origin of the long-range substrate effect in unentangled polymer material is still ambiguous. Herein, we investigated the propagation distances of the substrate effect (h*) by a fluorinated tracer-labeled method of two unentangled polymer films supported on silicon substrates: linear and ring poly(methyl methacrylate) films with relatively low molecular weights. The results indicate that the value of h* has a molecular weight dependence of h*∝N (N is the degree of polymerization) in the unentangled polymer films, while h*∝N^1/2 was presented as previously reported in the entangled films. A theoretical model, depending on the polymer/polymer intermolecular interaction, was proposed to describe the above long-range propagation behavior of the substrate effect and agrees with our experiment results very well. From the model, it revealed that the intermolecular friction determines the long-range propagation of the substrate effect in the unentangled system, but the intermolecular entanglement is the dominant role in entangled system. These results give us a deeper understanding of the long-range substrate effect. Full article

BODIPYs are bicyclic aromatic compounds with unique spectroscopic, photophysical, and chemical properties. This study aimed to find BODIPYs with characteristics biocompatible with human cell lines for possible use as imaging agents. Six BODIPY derivatives were synthesised with groups linked to boron, fluorine, phenol, or catechol, resulting in compounds with different physicochemical characteristics. NMR, absorption, and emission spectroscopy and mass spectrometry were subsequently used to characterise them. Afterwards, the biocompatibility of these compounds was evaluated using MTT, SRB, and cellular uptake assays in A549 and H1299 cell lines. Furthermore, a haemolysis assay was performed on human blood cells. To summarise the main results, BODIPYs 1 to 4 showed considerable fluorescence. In contrast, BODIPYs 5 and 6 showed very weak fluorescence, which could be related to the presence of the catechol group and its quenching properties. Regarding biocompatibility, all compounds had metabolic activity and viability above 80% and 70%, respectively. BODIPYs 3 and 6 presented the most consistent data, demonstrating good uptake and, in general, haemolytic activity below 25%. In conclusion, the cytotoxic effects of the compounds were not considerable, and the presence of cyclic alkoxides in BODIPYs 3 and 6 may introduce exciting features that should be highlighted for dual imaging for BODIPY 3 due to its fluorescence or for radioactive labelling in the case of both BODIPYs. Full article

Recently, growing evidence of the relationship between G-protein coupled receptor 44 (GPR44) and the inflammation-cancer system has garnered tremendous interest, while the exact role of GPR44 has not been fully elucidated. Currently, there is a strong and urgent need for the development of non-invasive in vivo GPR44 positron emission tomography (PET) radiotracers that can be used to aid the exploration of the relationship between inflammation and tumor biologic behavior. Accordingly, the choosing and radiolabeling of existing GPR44 antagonists containing a fluorine group could serve as a viable method to accelerate PET tracers development for in vivo imaging to this purpose. The present study aims to evaluate published (2000-present) indole-based and cyclopentenyl-indole-based analogues of the GPR44 antagonist to guide the development of fluorine-18 labeled PET tracers that can accurately detect inflammatory processes. The selected analogues contained a crucial fluorine nuclide and were characterized for various properties including binding affinity, selectivity, and pharmacokinetic and metabolic profile. Overall, 26 compounds with favorable to strong binding properties were identified. This review highlights the potential of GPR44 analogues for the development of PET tracers to study inflammation and cancer development and ultimately guide the development of targeted clinical therapies. Full article