A metal-free route to PET probesPositron emission tomography (PET) is a widely used imaging technique for medical diagnostics and pharmaceutical development. As the name implies, it requires tracers ...that emit positrons, typically through labeling with fluorine or carbon radioisotopes. W. Chen et al. devised a versatile technique to incorporate radioactive fluoride into aromatic rings. The metal-free photochemical method directly substitutes aryl carbon-hydrogen bonds with 18Ffluoride and so is particularly well suited to late-stage transformation of complex molecules into tracers.Science, this issue p. 1170Positron emission tomography (PET) plays key roles in drug discovery and development, as well as medical imaging. However, there is a dearth of efficient and simple radiolabeling methods for aromatic C–H bonds, which limits advancements in PET radiotracer development. Here, we disclose a mild method for the fluorine-18 (18F)–fluorination of aromatic C–H bonds by an 18FF− salt via organic photoredox catalysis under blue light illumination. This strategy was applied to the synthesis of a wide range of 18F-labeled arenes and heteroaromatics, including pharmaceutical compounds. These products can serve as diagnostic agents or provide key information about the in vivo fate of the labeled substrates, as showcased in preliminary tracer studies in mice.
Macrophages hold great potential in cancer drug delivery because they can sense chemotactic cues and home to tumors with high efficiency. However, it remains a challenge to load large amounts of ...therapeutics into macrophages without compromising cell functions. This study reports a silica‐based drug nanocapsule approach to solve this issue. The nanocapsule consists of a drug–silica complex filling and a solid silica sheath, and it is designed to minimally release drug molecules in the early hours of cell entry. While taken up by macrophages at high rates, the nanocapsules minimally affect cell migration in the first 6–12 h, buying time for macrophages to home to tumors and release drugs in situ. In particular, it is shown that doxorubicin (Dox) as a representative drug can be loaded into macrophages up to 16.6 pg per cell using this approach. When tested in a U87MG xenograft model, intravenously (i.v.) injected Dox‐laden macrophages show comparable tumor accumulation as untreated macrophages. Therapy leads to efficient tumor growth suppression, while causing little systematic toxicity. This study suggests a new cell platform for selective drug delivery, which can be readily extended to the treatment of other types of diseases.
Macrophages are exploited as a vehicle to deliver therapeutics to tumors. This is achieved by a silica‐based nanocapsule that can be engulfed by macrophages by large quantities but minimally release its payloads in the early hours of cell entry. This property buys time for macrophages to migrate to tumors to selectively kill cancer cells while causing minimal systemic toxicity.
Positron emission tomography (PET) is a powerful imaging technology that can visualize and measure metabolic processes in vivo and/or obtain unique information about drug candidates. The ...identification of new and improved molecular probes plays a critical role in PET, but its progress is somewhat limited due to the lack of efficient and simple labelling methods to modify biologically active small molecules and/or drugs. Current methods to radiofluorinate unactivated arenes are still relatively limited, especially in a simple and site-selective way. Here we disclose a method for constructing C-
F bonds through direct halide/
F conversion in electron-rich halo(hetero)arenes.
FF
is introduced into a broad spectrum of readily available aryl halide precursors in a site-selective manner under mild photoredox conditions. Notably, our direct
F/
F exchange method enables rapid PET probe diversification through the preparation and evaluation of an
F-labelled O-methyl tyrosine library. This strategy also results in the high-yielding synthesis of the widely used PET agent L-
FFDOPA from a readily available L-FDOPA analogue.
Innovative labeling methods to incorporate the short-lived positron emitter carbon-11(11C) into bioactive molecules are attractive for positron emission tomography (PET) tracer discovery. Herein, we ...report a direct C–H radiocyanation method that incorporates 11Ccyanide (11CN–) to a series of functional electron-rich arenes via photoredox catalysis. This photoredox-mediated radiocyanation can proceed in an aerobic environment and is not moisture sensitive, which allows for ease of reaction setup and for scalable synthesis of 11C-aryl nitriles from readily available precursors.
Recently, gadolinium-intercalated carbon dots (Gd@C-dots) have demonstrated potential advantages over traditional high-Z nanoparticles (HZNPs) as radiosensitizers due to their high stability, minimal ...metal leakage, and remarkable efficacy.
In this work, two Gd@C-dots formulations were fabricated which bore carboxylic acid (CA-Gd@C-dots) or amino group (pPD-Gd@C-dots), respectively, on the carbon shell. While it is critical to develop innovative nanomateirals for cancer therapy, determining their tumor accumulation and retention is equally important. Therefore, in vivo positron emission tomography (PET) was performed, which found that
Cu-labeled pPD-Gd@C-dots demonstrated significantly improved tumor retention (up to 48 h post injection) compared with CA-Gd@C-dots. Indeed, cell uptake of
Cu-pPD-Gd@C-dots reached close to 60% of total dose compared with ~ 5% of
Cu-CA-Gd@C-dots. pPD-Gd@C-dots was therefore further evaluated as a new radiosensitizer for non-small cell lung cancer treatment. While single dose radiation plus intratumorally injected pPD-Gd@C-dots did lead to improved tumor suppression, the inhibition effect was further improved with two doses of radiation. The persistent retention of pPD-Gd@C-dots in tumor region eliminates the need of reinjecting radiosensitizer for the second radiation.
PET offers a simple and straightforward way to study nanoparticle retention in vivo, and the selected pPD-Gd@C-dots hold great potential as an effective radiosensitizer.
Several studies have suggested that neurotensin receptors (NTRs) and neurotensin (NT) greatly affect the growth and survival of pancreatic ductal adenocarcinoma (PDAC). Developing NTR-targeted PET ...probes could therefore be important for the management of a pancreatic cancer patient by providing key information on the NTR expression profile noninvasively. Despite the initial success on the synthesis of 18F-labeled NT PET probes, the labeling procedure generally requires lengthy steps including azeotropic drying of 18F. Using a straightforward chelation method, here we report the simple preparation of aluminum-18F-NOTA-NT starting from aqueous 18F. The cell binding test demonstrated that 19FAlF-NOTA-NT maintained high receptor-binding affinity to NTR1. This probe was then further evaluated in NTR1 positive pancreatic tumor models (AsPC-1 and PANC-1). After the administration of 18FAlF-NOTA-NT, small animal PET studies showed a high contrast between tumor and background in both models at 1 and 4 h time points. A blocking experiment was performed to demonstrate the receptor specificity: the tumor uptake in AsPC1 without and with blocking agent was 1.0 ± 0.2 and 0.1 ± 0.0%ID/g, respectively, at 4 h post injection. In summary, a NTR specific PET agent, 18FAlF-NOTA-NT, was prepared through the simple chelation method. This NTR-targeted PET probe may not only be used to detect NTR1 positive pancreatic tumors (diagnosis), but also it may be fully integrated to NTR target therapy leading to personalized medicine (theranostic).
Power transformer is an essential component for the stable and reliable operation of electrical power grid. The traditional transformer fault diagnostic methods based on dissolved gas analysis are ...limited due to the low accuracy of fault identification. In this study, an effective transformer fault diagnosis system is proposed to improve identification accuracy. The proposed approach combines an improved genetic algorithm (IGA) with the XGBoost to form a hybrid diagnosis network. The combination of the improved genetic algorithm and the XGBoost (IGA-XGBoost) forms the basic unit of the proposed method, which decomposes and reconstructs the transformer fault recognition problem into several minor problems IGA-XGBoosts can solve. The results of simulation experiments show that the IGA performs excellently in the combined optimization of input feature selection and the XGBoost parameter, and the proposed method can accurately identify the transformer fault types with an average accuracy of 99.2%. Compared to IEC ratios, dual triangle, support vector machine and common vector approach the diagnostic accuracy of the proposed method is improved by 30.2, 47.2, 11.2, and 3.6%, respectively. The proposed method can be a potential solution to identify the transformer fault types.
Human immunodeficiency virus type-1 (HIV-1) and opiates cause long-term inflammatory insult to the central nervous system (CNS) and worsen disease progression and HIV-1-related neuropathology. The ...combination of these proinflammatory factors reflects a devastating problem as opioids have high abuse liability and continue to be prescribed for certain patients experiencing HIV-1-related pain.
Here, we examined the impact of chronic (3-month) HIV-1 transactivator of transcription (Tat) exposure to short-term (8-day), escalating morphine in HIV-1 Tat transgenic mice that express the HIV-1 Tat protein in a GFAP promoter-regulated, doxycycline (DOX)-inducible manner. In addition to assessing morphine-induced tolerance in nociceptive responses organized at spinal (i.e., tail-flick) and supraspinal (i.e., hot-plate) levels, we evaluated neuroinflammation via positron emission tomography (PET) imaging using the
F-PBR111 ligand, immunohistochemistry, and cytokine analyses. Further, we examined endocannabinoid (eCB) levels, related non-eCB lipids, and amino acids via mass spectrometry. RESULTS: Tat-expressing Tat(+) transgenic mice displayed antinociceptive tolerance in the tail withdrawal and hot-plate assays compared to control mice lacking Tat Tat(-). This tolerance was accompanied by morphine-dependent increases in Iba-1 ± 3-nitrotryosine immunoreactive microglia, and alterations in pro- and anti-inflammatory cytokines, and chemokines in the spinal cord and striatum, while increases in neuroinflammation were absent by PET imaging of
F-PBR111 uptake. Tat and morphine exposure differentially affected eCB levels, non-eCB lipids, and specific amino acids in a region-dependent manner. In the striatum, non-eCB lipids were significantly increased by short-term, escalating morphine exposure, including peroxisome proliferator activator receptor alpha (PPAR-α) ligands N-oleoyl ethanolamide (OEA) and N-palmitoyl ethanolamide (PEA), as well as the amino acids phenylalanine and proline. In the spinal cord, Tat exposure increased amino acids leucine and valine, while morphine decreased levels of tyrosine and valine but did not affect eCBs or non-eCB lipids.
Overall results demonstrate that 3 months of Tat exposure increased morphine tolerance and potentially innate immune tolerance evidenced by reductions in specific cytokines (e.g., IL-1α, IL-12p40) and microglial reactivity. In contrast, short-term, escalating morphine exposure acted as a secondary stressor revealing an allostatic shift in CNS baseline inflammatory responsiveness from sustained Tat exposure.
The radiofluorination of N-heterocyclic carbene (NHC) boron trifluoride adducts affords novel (18)F-positron emission tomography probes which resist hydrolytic fluoride release. The labelling ...protocol relies on an (18)F-(19)F isotopic exchange reaction promoted by the Lewis acid SnCl4. Modification of the NHC backbone with a maleimide functionality provides access to a model peptide conjugate which shows no evidence of defluorination when imaged in vivo.
MerTK (Mer tyrosine kinase), a receptor tyrosine kinase, is ectopically or aberrantly expressed in numerous human hematologic and solid malignancies. Although a variety of MerTK targeting therapies ...are being developed to enhance outcomes for patients with various cancers, the sensitivity of tumors to MerTK suppression may not be uniform due to the heterogeneity of solid tumors and different tumor stages. In this report, we develop a series of radiolabeled agents as potential MerTK PET (positron emission tomography) agents. In our initial in vivo evaluation,
F-
showed prominent uptake rate (4.79 ± 0.24%ID/g) in B16F10 tumor-bearing mice. The tumor to muscle ratio reached 1.86 and 3.09 at 0.5 and 2 h post-injection, respectively. In summary,
F-
is a promising PET agent for MerTK imaging and is worth further evaluation in future studies.
PDF
![Development of [18F]AlF-NOT...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1543-8384/small "Development of [18F]AlF-NOTA-NT as PET Agents of Neurotensin Receptor‑1 Positive Pancreatic Cancer")
![[(18)F]-NHC-BF3 adducts as ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1359-7345/small "[(18)F]-NHC-BF3 adducts as water stable radio-prosthetic groups for PET imaging")
