Harvesting sunlight to drive carbon dioxide (CO
) valorisation represents an ideal concept to support a sustainable and carbon-neutral economy. While the photochemical reduction of CO
to carbon ...monoxide (CO) has emerged as a hot research topic, the full CO
-to-CO conversion remains an often-overlooked criterion that prevents a productive and direct valorisation of CO into high-value-added chemicals. Herein, we report a photocatalytic process that unlocks full and fast CO
-to-CO conversion (<10 min) and its straightforward valorisation into human health related field of radiochemistry with carbon isotopes. Guided by reaction-model-based kinetic simulations to rationalize reaction optimisations, this manifold opens new opportunities for the direct access to
C- and
C-labeled pharmaceuticals from their primary isotopic sources
CCO
and
CCO
.
Summary
Objective
Mesiotemporal lobe epilepsy is the most common type of drug‐resistant partial epilepsy, with a specific history that often begins with status epilepticus due to various neurological ...insults followed by a silent period. During this period, before the first seizure occurs, a specific lesion develops, described as unilateral hippocampal sclerosis (HS). It is still challenging to determine which drugs, administered at which time point, will be most effective during the formation of this epileptic process. Neuroinflammation plays an important role in pathophysiological mechanisms in epilepsy, and therefore brain inflammation biomarkers such as translocator protein 18 kDa (TSPO) can be potent epilepsy biomarkers. TSPO is associated with reactive astrocytes and microglia. A unilateral intrahippocampal kainate injection mouse model can reproduce the defining features of human temporal lobe epilepsy with unilateral HS and the pattern of chronic pharmacoresistant temporal seizures. We hypothesized that longitudinal imaging using TSPO positron emission tomography (PET) with 18F‐DPA‐714 could identify optimal treatment windows in a mouse model during the formation of HS.
Methods
The model was induced into the right dorsal hippocampus of male C57/Bl6 mice. Micro‐PET/computed tomographic scanning was performed before model induction and along the development of the HS at 7 days, 14 days, 1 month, and 6 months. In vitro autoradiography and immunohistofluorescence were performed on additional mice at each time point.
Results
TSPO PET uptake reached peak at 7 days and mostly related to microglial activation, whereas after 14 days, reactive astrocytes were shown to be the main cells expressing TSPO, reflected by a continuing increased PET uptake.
Significance
TSPO‐targeted PET is a highly potent longitudinal biomarker of epilepsy and could be of interest to determine the therapeutic windows in epilepsy and to monitor response to treatment.
To evaluate whether striatal (18)FMNI-659 PET imaging of phosphodiesterase 10A (PDE10) serves as a sensitive and reliable biomarker of striatal neurodegeneration in a longitudinal cohort of ...participants with early Huntington disease (HD).
A cohort of participants with HD, including both participants premanifest or manifest with motor signs, underwent clinical assessments, genetic determination, and 2 (18)FMNI-659 PET imaging sessions approximately 1 year apart. Eleven healthy control (HC) participants underwent clinical assessments and (18)FMNI-659 PET imaging once. Striatal binding potentials (BPnd) were estimated for brain regions of interest, specifically within the basal ganglia, and compared between baseline and follow-up imaging. Clinical measures of HD severity were assessed at each visit.
Eight participants with HD (6 manifest; 2 premanifest) participated. Of those with manifest HD, all had relatively early stage disease (stage 1, n = 2; stage 2, n = 4) and a Unified Huntington's Disease Rating Scale total motor score <45. As expected, the HD cohort as a whole had a reduction in the basal ganglia BPnd to approximately 50% of that seen in HC. On follow-up scans, (18)FMNI-659 uptake declined in the putamen and caudate nucleus in all 8 participants. The mean annualized rates of decline in signal in the caudate, putamen, and globus pallidus and the putamen were 16.6%, 6.9%, and 5.8%, respectively. In HC, the annualized reduction in signal in striatal regions was less than 1%.
Longitudinal data in this small cohort of participants with early HD support (18)FMNI-659 PET imaging of PDE10 as a useful biomarker to track HD disease progression.
The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be ...controlled by ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier. We used (11)C-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain.
(11)C-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. (11)C-metoclopramide brain kinetics were compared using PET in rats (n = 4-5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The (11)C-metoclopramide brain distribution (VT based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio-high-performance liquid chromatography analysis.
(11)C-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline (11)C-metoclopramide brain kinetics (VT = 2.28 ± 0.32 and 2.04 ± 0.19 mL⋅cm(-3) using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced microdose (11)C-metoclopramide VT (7.80 ± 1.43 mL⋅cm(-3)) with a 4.4-fold increase in K1 (influx rate constant) and a 2.3-fold increase in binding potential (k3/k4) in the 2-tissue-compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (VT = 6.28 ± 0.48 mL⋅cm(-3)) with a 2.0-fold increase in K1 and a 2.2-fold decrease in k2 (efflux rate), with no significant impact on binding potential. In this situation, only parent (11)C-metoclopramide could be detected in the brains of P-gp-inhibited rats.
(11)C-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood-brain barrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx but also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients.
Organic Anion-Transporting Polypeptides (OATPs) are known to control the liver uptake of many drugs. Non-hepatic expression of OATPs has been reported although functional importance for whole-body ...pharmacokinetics (WBPK) remains unknown. Glyburide is a well described substrate of several hepatic and non-hepatic OATPs. Dynamic whole-body positron emission tomography (DWB-PET) with 11Cglyburide was performed in humans for determination of the importance of OATPs for liver uptake and WBPK. Seven healthy male subjects (24.7 ± 3.2 years) underwent 11Cglyburide PET scan with concomitant blood sampling. All subjects underwent baseline 11Cglyburide PET scan. Five subjects underwent a subsequent 11Cglyburide PET scan after infusion of the potent OATP inhibitor rifampicin (9 mg/kg i.v.). The transfer constant (kuptake) of 11Cglyburide from blood to the liver was estimated using the integration plot method. The tissue exposure of 11Cglyburide was described by the area under the time-activity curve (AUC) and corresponding tissue/blood ratio (AUCR). 11Cglyburide was barely metabolized in both the baseline and rifampicin conditions. Parent (unmetabolized) 11Cglyburide accounted for > 90 % of the plasma radioactivity. Excellent correlation was found between radioactive counting in arterial blood samples and in the image-derived input function, in both the baseline and rifampicin conditions (R2 = 97.9 %, p < 0.01). 11Cglyburide predominantly accumulated in the liver. Rifampicin decreased liver kuptake by 77.3 ± 7.3 %, which increased exposure in blood, kidneys, spleen, myocardium and brain (p < 0.05). No significant change in AUCR was observed except in the liver (p < 0.01). 11Cglyburide benefits from metabolic stability and high sensitivity to OATP inhibition which enables quantitative determination of OATP function. DWB-PET suggests negligible role for non-hepatic OATPs in controlling the tissue distribution of 11Cglyburide.
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•Organic Anion-Transporting Polypeptides (OATP) form a family of influx transporters.•Importance of hepatic and non-hepatic OATP on drug delivery in humans is not known.•Whole-body PET imaging using the OATP substrate 11C-glyburide was performed in humans.•11C-glyburide benefits from unmet imaging properties to explore OATP function in humans.•PET data suggest a liver-selective importance of OATP in controlling drug delivery.
Diffuse intrinsic pontine gliomas (DIPG), the first cause of cerebral pediatric cancer death, will greatly benefit from specific and non-invasive biomarkers for patient follow-up and monitoring of ...drug efficacy. Since biopsies are challenging for brain tumors, molecular imaging may be a technique of choice to target and follow tumor evolution. So far, MR remains the imaging technique of reference for DIPG, although it often fails to define the extent of tumors, an essential parameter for therapeutic efficacy assessment. Thanks to its high sensitivity, positron emission tomography (PET) offers a unique way to target specific biomarkers in vivo. We demonstrated in a patient-derived orthotopic xenograft (PDOX) model in the rat that the translocator protein of 18 kDa (TSPO) may be a promising biomarker for monitoring DIPG tumors. We studied the distribution of 18F-DPA-714, a TSPO radioligand, in rats inoculated with HSJD-DIPG-007 cells. The primary DIPG human cell line HSJD-DIPG-007 highly represents this pediatric tumor, displaying the most prevalent DIPG mutations, H3F3A (K27M) and ACVR1 (R206H). Kinetic modeling and parametric imaging using the brain 18F-DPA-714 PET data enabled specific delineation of the DIPG tumor area, which is crucial for radiotherapy dose management.
A series of novel triazole derivative pyridine‐based polyamino–polycarboxylate ligands has been synthesized for lanthanide complexation. This versatile platform of chelating agents combines ...advantageous properties for both magnetic resonance (MR) and optical imaging applications of the corresponding Gd3+ and near‐infrared luminescent lanthanide complexes. The thermodynamic stability constants of the Ln3+ complexes, as assessed by pH potentiometric measurements, are in the range log KLnL=17–19, with a high selectivity for lanthanides over Ca2+, Cu2+, and Zn2+. The complexes are bishydrated, an important advantage to obtain high relaxivities for the Gd3+ chelates. The water exchange of the Gd3+ complexes (kex298=7.7–9.3×106 s−1) is faster than that of clinically used magnetic resonance imaging (MRI) contrast agents and proceeds through a dissociatively activated mechanism, as evidenced by the positive activation volumes (ΔV≠=7.2–8.8 cm3 mol−1). The new triazole ligands allow a considerable shift towards lower excitation energies of the luminescent lanthanide complexes as compared to the parent pyridinic complex, which is a significant advantage in the perspective of biological applications. In addition, they provide increased epsilon values resulting in a larger number of emitted photons and better detection sensitivity. The most conjugated system PheTPy, bearing a phenyl–triazole pendant on the pyridine ring, is particularly promising as it displays the lowest excitation and triplet‐state energies associated with good quantum yields for both Nd3+ and Yb3+ complexes. Cellular and in vivo toxicity studies in mice evidenced the non‐toxicity and the safe use of such bishydrated complexes in animal experiments. Overall, these pyridinic ligands constitute a highly versatile platform for the simultaneous optimization of both MRI and optical properties of the Gd3+ and the luminescent lanthanide complexes, respectively.
Bimodal application: Pyridine‐based polyamino–polycarboxylate ligands (see figure) ensure non‐toxicity as well as advantageous magnetic and luminescence properties for the corresponding Gd3+ and near‐infrared‐emitting lanthanide complexes.
The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant ...age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls.
Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy.
We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients.
The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.
A robust, click‐chemistry‐inspired procedure for radiolabeling of cyclic ureas was developed. This protocol, suitable for all carbon isotopes (11C, 13C, 14C), is based on the direct functionalization ...of carbon dioxide: the universal building block for carbon radiolabeling. The strategy is operationally simple and reproducible in different radiochemistry centers, exhibits remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity as compared to previously reported systems. With this procedure, a variety of pharmaceuticals and an unprotected peptide were labeled with high radiochemical efficiency.
Label with a click: A Staudinger/aza‐Wittig approach to carbon labeling inspired by click chemistry has been developed that is suitable for all carbon isotopes (11C, 13C, 14C). Thus, a variety of pharmaceuticals and an unprotected peptide were labeled with high radiochemical efficiency by urea formation between o‐azidoanilines and isotopically labeled carbon dioxide (see picture).
Neuropathological studies showed early locus coeruleus (LC) neuronal loss associated with tauopathy in Alzheimer’s Disease (AD). We used the LC signal intensity (LC‐I) on 3T MRI to assess the LC ...integrity in AD (n = 37) and controls (n = 17). The LC‐I was decreased in AD regardless of typical (amnesic) and atypical presentation (logopenic aphasia/visuo‐spatial deficit), from the prodromal stage, and independently of the amyloid load measured by PiB‐PET. The LC‐I was correlated with memory performance of typical AD. This supports the pathophysiological model in which the LC plays a critical role in AD and may thus be a potential therapeutic target.
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