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The predictions for the atmospheric neutrino flux at high energies strongly depend on the contribution of prompt neutrinos, which are determined by the production of charmed mesons in the atmosphere at very forward rapidities. In this paper we estimate the related cross sections taking into account the presence of an intrinsic charm (IC) component in the proton wave function and the QCD dynamics modified by the onset of saturation effects. The impact on the predictions for the prompt neutrino flux is investigated assuming different values for the probability to find the IC in the nucleon ( P ic ). We demonstrate that for P ic ∼ 1%, the IC component dominates the high-energy prompt neutrino flux. A first comparison with the IceCube data is performed and upper limits on the amount of IC are obtained for the linear and nonlinear descriptions of the QCD dynamics. [ABSTRACT FROM AUTHOR]

A phenomenological study of the exclusive vector meson photoproduction within the discrete BFKL approach is performed. We estimate the BFKL amplitude in terms of a discrete set of eigenfunctions and use the HERA F 2 data to constrain the free parameters of the model. As a consequence, we derive a parameter free prediction of the energy dependence of the exclusive vector meson cross section. We demonstrate that the HERA and LHCb data for the exclusive J / Ψ and Υ photoproduction are quite well describe in a large energy range. However, the model overestimates the precise LHCb data for the smallest values of x , which can be interpreted as an indication of the onset of nonlinear (saturation) effects in the QCD dynamics. [ABSTRACT FROM AUTHOR]

A phenomenological study of the two-photon reaction within the discrete BFKL approach is performed. We estimate the BFKL amplitude in terms of a discrete set of eigenfunctions and use the HERA F 2 p data to constrain the free parameters of the model. As a consequence, we derive a parameter free prediction of the energy dependence of the total γ γ cross-section and the Bjorken- x dependence of the photon structure function. We demonstrate that the LEP data is quite well described by the discrete BFKL approach and that experimental data from the future e + e − colliders can be useful to constrain the description of the QCD dynamics at high energies. [ABSTRACT FROM AUTHOR]

The description of the densest neutron stars found in Nature depends on the understanding of the physical concepts present in General Relativity and in the theory of strong interactions - the Quantum Chromodynamics. In this work we review the essential concepts to describe strange stars, constituted by quarks up, down and strange, which is one of the alternatives for the composition of ultradense neutron stars. We will review the Bodmer-Witten-Terazawa hypothesis, which states that the strange matter is absolutely stable in relation to the ordinary nuclear matter, and discuss the basic properties that characterize strange stars. Our goal is to present the necessary concepts to understand this important theme of Astroparticles. [ABSTRACT FROM AUTHOR]

The description of the heavy meson production at large energies and forward rapidities at the LHC is fundamental to derive realistic predictions of the prompt atmospheric neutrino flux at the IceCube Observatory. In particular, the prompt tau neutrino flux is determined by the decay of D s mesons produced in cosmic ray–air interactions at high energies and large values of the Feynman- x F variable. Recent data of the LHCb Collaboration indicate a production asymmetry for D s + and D s − mesons, which cannot be explained in terms of the standard modeling of the hadronization process. In this paper we demonstrate that this asymmetry can be described assuming an asymmetric strange sea (s (x) ≠ s ¯ (x)) in the proton wave function and taking into account the dominant charm and subdominant strange fragmentation into D s mesons. Moreover, we show that the strange quark fragmentation contribution is dominant at large- x F (≥0.3). The prompt ν τ flux is calculated and the enhancement associated with the strange quark fragmentation contribution, disregarded in previous calculations, is estimated. The considered scenario leads to quite sizable enhancement of the high-energy τ -neutrino flux. [ABSTRACT FROM AUTHOR]

One of the main goals of future electron-ion colliders is to improve our understanding of the structure of hadrons. In this letter, we study the exclusive η c production by γ ⁎ γ interactions in eA collisions and demonstrate that future experimental analysis of this process can be used to improve the description of the η c transition form factor. The rapidity, transverse momentum and photon virtuality distributions are estimated considering the energy and target configurations expected to be present at the EIC, EicC and LHeC and assuming different predictions for the light-front wave function of the η c meson. Our results indicate that the electron-ion colliders can be considered an alternative to providing supplementary data to those obtained in e − e + colliders. [ABSTRACT FROM AUTHOR]

Inhibitorsof LeishmaniaN-myristoyltransferase(NMT), a potential target for thetreatment of leishmaniasis, obtained from a high-throughput screen,were resynthesized to validate activity. Crystal structures boundto Leishmania majorNMT were obtained,and the active diastereoisomer of one of the inhibitors was identified.On the basis of structural insights, enzyme inhibition was increased40-fold through hybridization of two distinct binding modes, resultingin novel, highly potent Leishmania donovaniNMT inhibitors with good selectivity over the human enzyme. [ABSTRACT FROM AUTHOR]

Several new boron dipyrromethene/ N, N-dimethylaminopyridine (BODIPY-DMAP) assemblies were synthesized as precursors for bimodal imaging probes (optical imaging, OI/positron emission tomography, PET). The photophysical properties of the new compounds were also studied. The first proof-of-concept was obtained with the preparation of several new BODIPY-labeled bombesins and evaluation of the affinity for bombesin receptors by using a competition binding assay. Fluorination reactions were investigated on DMAP-BODIPY precursors as well as on DMAP-BODIPY-labeled bombesins. Chemical modifications on the BODIPY core were also performed to obtain luminescent dyes emitting in the therapeutic window (650-900 nm), suitable for in vivo imaging, making these compounds promising precursors for PET/optical dual-modality imaging agents. [ABSTRACT FROM AUTHOR]

N-Myristoyltransferase (NMT) is a prospective drug target against parasitic protozoa. Herein we report the successful discovery of a series of Plasmodium vivax NMT inhibitors by high-throughput screening. A high-resolution crystal structure of the hit compound in complex with NMT was obtained, allowing understanding of its novel binding mode. A set of analogues was designed and tested to define the chemical groups relevant for activity and selectivity. [ABSTRACT FROM AUTHOR]

Cyclic peptide antagonist c[YYDEGLEE]-NH2, which disrupts the interaction between vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), represents a promising tool in the fight against cancer and age-related macular degeneration. Furthermore, coupled to a cyclen derivative, this ligand could be used as a medicinal imaging agent. Nevertheless, before generating such molecular probes, some preliminary studies need to be undertaken in order to define the more suitable positions for introduction of the cyclen macrocycle. Through an Ala-scan study on this peptide, we identified its binding motif, and an NMR study highlights its binding sites on the VEGFR-1D2 Ig-like domain. Guided by the structural relationship results deduced from the effect of the peptides on endothelial cells, new peptides were synthesized and grafted on beads. Used in a pull-down assay, these new peptides trap the VEGFRs, thus confirming that the identified amino acid positions are suitable for further derivatization. [ABSTRACT FROM AUTHOR]

Abstract: Cyclic peptides were obtained, on-resin, by the copper (I) catalysed 1,3-dipolar cycloaddition of azides and alkynes. The reaction led exclusively to the formation of the expected cyclomonomeric products which acted as ligands of the Vascular Endothelial Growth Factor receptor 1. [Copyright &y& Elsevier]

Abstract: N-myristoylation is the irreversible attachment of a C14 fatty acid, myristic acid, to the N-terminal glycine of a protein via formation of an amide bond. This modification is catalyzed by myristoyl–coenzyme A (CoA):protein N-myristoyltransferase (NMT), an enzyme ubiquitous in eukaryotes that is up-regulated in several cancers. Here we report a sensitive fluorescence-based assay to study the enzymatic activity of human NMT1 and NMT2 based on detection of CoA by 7-diethylamino-3-(4-maleimido-phenyl)-4-methylcoumarin. We also describe expression and characterization of NMT1 and NMT2 and assay validation with small molecule inhibitors. This assay should be broadly applicable to NMTs from a range of organisms. [Copyright &y& Elsevier]

Background: The resistance of glioblastoma stem cells (GSCs) to treatment is one of the causes of glioblastoma (GBM) recurrence. Endothelin A receptor (ETA) overexpression in GSCs constitutes an attractive biomarker for targeting this cell subpopulation, as illustrated by several clinical trials evaluating the therapeutic efficacy of endothelin receptor antagonists against GBM. In this context, we have designed an immunoPET radioligand combining the chimeric antibody targeting ETA, chimeric-Rendomab A63 (xiRA63), with 89Zr isotope and evaluated the abilities of xiRA63 and its Fab (ThioFab-xiRA63) to detect ETA+ tumors in a mouse model xenografted orthotopically with patient-derived Gli7 GSCs. Results: Radioligands were intravenously injected and imaged over time by µPET-CT imaging. Tissue biodistribution and pharmacokinetic parameters were analyzed, highlighting the ability of [89Zr]Zr-xiRA63 to pass across the brain tumor barrier and achieve better tumor uptake than [89Zr]Zr-ThioFab-xiRA63. Conclusions: This study shows the high potential of [89Zr]Zr-xiRA63 in specifically targeting ETA+ tumors, thus raising the possibility of detecting and treating ETA+ GSCs, which could improve the management of GBM patients. [ABSTRACT FROM AUTHOR]

Purpose: The present study aims at developing and evaluating an urea-based prostate specific membrane antigen (PSMA) inhibitor suitable for labeling with 111In for SPECT and intraoperative applications as well as 68Ga and 64Cu for PET imaging. Methods: The PSMA-based inhibitor-lysine-urea-glutamate-coupled to the spacer Phe-Phe-D-Lys(suberoyl) and functionalized with the enantiomerically pure prochelator (R)-1-(1-carboxy-3-carbotertbutoxypropyl)-4,7-carbotartbutoxymethyl)-1,4,7-triazacyclononane ((R)-NODAGA(tBu)3), to obtain (R)-NODAGA-Phe-Phe-D-Lys(suberoyl)-Lys-urea-Glu (CC34). CC34 was labeled with 111In, 68Ga and 64Cu. The radioconjugates were further evaluated in vitro and in vivo in LNCaP xenografts by biodistribution and PET studies. Biodistribution studies were also performed with 68Ga-HBED-CC-PSMA (HBED-CC: N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid) and 111In-PSMA-617 for comparison. Results: 68Ga-CC34, 64Cu-CC34, and 111In-CC34 were prepared in radiochemical purity >95%. 68/natGa-CC34, 64/natCu-CC34, 111/natIn-CC34, 68/natGa-HBED-CC-PSMA, and 111/natIn-PSMA-617 exhibited high affinity for the LNCaP cells, with Kd values of 19.3±2.5 nM, 27.5±2.7 nM, 5.5±0.9 nM, 2.9±0.6 nM and 5.4±0.8 nM, respectively. They revealed comparable internalization profiles with approximately 75% of the total cell associated activity internalized after 3 h of incubation. 68Ga-CC34 showed very high stability after its administration in mice. Tumor uptake of 68Ga-CC34 (14.5±2.9% IA/g) in LNCaP xenografts at 1 h p.i. was comparable to 68Ga-HBED-CC-PSMA (15.8±1.4% IA/g) (P = 0.67). The tumor-to-normal tissue ratios at 1 and 2 h p.i of 68Ga-CC34 were also comparable to 68Ga-HBED-CC-PSMA (P>0.05). Tumor uptake of 111In-CC34 (28.5±2.6% IA/g) at 1 h p.i. was lower than 111In-PSMA-617 (52.1±6.5% IA/g) (P = 0.02). The acquisition of PET-images with 64Cu-CC34 at later time points showed wash-out from the kidneys, while tumor uptake still remained relatively high. This resulted in an increased tumor-to-kidney ratio over time. Conclusions: 68Ga-CC34 is comparable to 68Ga-HBED-CC-PSMA in terms of tumor uptake and tumor to normal tissue ratios. 64Cu-CC34 could enable high contrast imaging of PSMA positive tissues characterized by elevated expression of PSMA or when delayed imaging is required. 64Cu-CC34 is currently being prepared for clinical translation. [ABSTRACT FROM AUTHOR]

Summary: Protein-protein interactions play a central role in medicine, and their modulation with small organic compounds remains an enormous challenge. Because it has been noted that the macromolecular complexes modulated to date have a relatively pronounced binding cavity at the interface, we decided to perform screening experiments over the vascular endothelial growth factor receptor (VEGFR), a validated target for antiangiogenic treatments with a very flat interface. We focused the study on the VEGFR-1 D2 domain, and 20 active compounds were identified. These small compounds contained a (3-carboxy-2-ureido)thiophen unit and had IC50 values in the low micromolar range. The most potent compound inhibited the VEGF-induced VEGFR-1 transduction pathways. Our findings suggest that our best hit may be a promising scaffold to probe this macromolecular complex and for the development of treatments of VEGFR-1-dependent diseases. [ABSTRACT FROM AUTHOR]

Lately, zirconium-89 has shown great promise as a radionuclide for PET applications of long circulating biomolecules. Here, the design and synthesis of protracted and long-lived GLP-1 receptor agonists conjugated to desferrioxamine and labelled with zirconium-89 is presented with the purpose of studying their in vivo distribution by PET imaging. The labelled conjugates were evaluated and compared to a non-labelled GLP-1 receptor agonist in both in vitro and in vivo assays to certify that the modification did not significantly alter the peptides' structure or function. Finally, the zirconium-89 labelled peptides were employed in PET imaging, providing visual verification of their in vivo biodistribution. The evaluation of the radiolabelled peptides and comparison to their non-labelled parent peptide was performed by in vitro assays measuring binding and agonistic potency to the GLP-1 receptor, physicochemical studies aiming at elucidating change in peptide structure upon bioconjugation and labelling as well as an in vivo food in-take study illustrating the compounds' pharmacodynamic properties. The biodistribution of the labelled GLP-1 analogues was determined by ex vivo biodistribution and in vivo PET imaging. The results indicate that it is surprisingly feasible to design and synthesize a protracted, zirconium-89 labelled GLP-1 receptor agonist without losing in vitro potency or affinity as compared to a non-labelled parent peptide. Physicochemical properties as well as pharmacodynamic properties are also maintained. The biodistribution in rats shows high accumulation of radiolabelled peptide in well-perfused organs such as the liver, kidney, heart and lungs. The PET imaging study confirmed the findings from the biodistribution study with a significant high uptake in kidneys and presence of activity in liver, heart and larger blood vessels. This initial study indicates the potential to monitor the in vivo distribution of long-circulating incretin hormones using zirconium-89 based PET. Unlabelled Image [ABSTRACT FROM AUTHOR]

Purpose: Currently, the most commonly used chelator for labelling antibodies with 89Zr for immunoPET is desferrioxamine B (DFO). However, preclinical studies have shown that the limited in vivo stability of the 89Zr-DFO complex results in release of 89Zr, which accumulates in mineral bone. Here we report a novel chelator DFOcyclo*, a preorganized extended DFO derivative that enables octacoordination of the 89Zr radiometal. The aim was to compare the in vitro and in vivo stability of [89Zr]Zr-DFOcyclo*, [89Zr]Zr-DFO* and [89Zr]Zr-DFO. Methods: The stability of 89Zr-labelled chelators alone and after conjugation to trastuzumab was evaluated in human plasma and PBS, and in the presence of excess EDTA or DFO. The immunoreactive fraction, IC50, and internalization rate of the conjugates were evaluated using HER2-expressing SKOV-3 cells. The in vivo distribution was investigated in mice with subcutaneous HER2+ SKOV-3 or HER2− MDA-MB-231 xenografts by PET/CT imaging and quantitative ex vivo tissue analyses 7 days after injection. Results: 89Zr-labelled DFO, DFO* and DFOcyclo* were stable in human plasma for up to 7 days. In competition with EDTA, DFO* and DFOcyclo* showed higher stability than DFO. In competition with excess DFO, DFOcyclo*-trastuzumab was significantly more stable than the corresponding DFO and DFO* conjugates (p < 0.001). Cell binding and internalization were similar for the three conjugates. In in vivo studies, HER2+ SKOV-3 tumour-bearing mice showed significantly lower bone uptake (p < 0.001) 168 h after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (femur 1.5 ± 0.3%ID/g, knee 2.1 ± 0.4%ID/g) or [89Zr]Zr-DFO*-trastuzumab (femur 2.0 ± 0.3%ID/g, knee 2.68 ± 0.4%ID/g) than after injection with [89Zr]Zr-DFO-trastuzumab (femur 4.5 ± 0.6%ID/g, knee 7.8 ± 0.6%ID/g). Blood levels, tumour uptake and uptake in other organs were not significantly different at 168 h after injection. HER2− MDA-MB-231 tumour-bearing mice showed significantly lower tumour uptake (p < 0.001) after injection with [89Zr]Zr-DFOcyclo*-trastuzumab (16.2 ± 10.1%ID/g) and [89Zr]Zr-DFO-trastuzumab (19.6 ± 3.2%ID/g) than HER2+ SKOV-3 tumour-bearing mice (72.1 ± 14.6%ID/g and 93.1 ± 20.9%ID/g, respectively), while bone uptake was similar. Conclusion: 89Zr-labelled DFOcyclo* and DFOcyclo*-trastuzumab showed higher in vitro and in vivo stability than the current commonly used 89Zr-DFO-trastuzumab. DFOcyclo* is a promising candidate to become the new clinically used standard chelator for 89Zr immunoPET. [ABSTRACT FROM AUTHOR]

Abstract: Dual‐labeled biomolecules constitute a new generation of bioconjugates with promising applications in therapy and diagnosis. Unfortunately, the development of these new families of biologics is hampered by the technical difficulties associated with their construction. In particular, the site specificity of the conjugation is critical as the number and position of payloads can have a dramatic impact on the pharmacokinetics of the bioconjugate. Herein, we introduce dichlorotetrazine as a trivalent platform for the selective double modification of proteins on cysteine residues. This strategy is applied to the dual labeling of albumin with a macrocyclic chelator for nuclear imaging and a fluorescent probe for fluorescence imaging. [ABSTRACT FROM AUTHOR]

Abstract: Dual‐labeled biomolecules constitute a new generation of bioconjugates with promising applications in therapy and diagnosis. Unfortunately, the development of these new families of biologics is hampered by the technical difficulties associated with their construction. In particular, the site specificity of the conjugation is critical as the number and position of payloads can have a dramatic impact on the pharmacokinetics of the bioconjugate. Herein, we introduce dichlorotetrazine as a trivalent platform for the selective double modification of proteins on cysteine residues. This strategy is applied to the dual labeling of albumin with a macrocyclic chelator for nuclear imaging and a fluorescent probe for fluorescence imaging. [ABSTRACT FROM AUTHOR]

In molecular imaging, multimodal imaging agents can provide complementary information, for improving the accuracy of disease diagnosis or enhancing patient management. In particular, optical/nuclear imaging may find important preclinical and clinical applications. To simplify the preparation of dual-labeled imaging agents, we prepared versatile monomolecular multimodal imaging probe (MOMIP) platforms containing both a fluorescent dye (BODIPY) and a metal chelator (polyazamacrocycle). One of the MOMIP was conjugated to a cyclopeptide (i.e., octreotide) and radiolabeled with 111In. In vitro and in vivo studies of the resulting bioconjugate were conducted, highlighting the potential of these BODIPY-based bimodal probes. This work also confirmed that the biovector and/or the bimodal probes must be chosen carefully, due to the impact of the MOMIP on the overall properties of the resulting imaging agent. [ABSTRACT FROM AUTHOR]

Four new red BODIPY–gold(i) theranostic compounds were synthesized. Some of them were vectorized by tethering a biovector (glucose or bombesin derivatives) to the metallic center. Their photophysical properties were studied. Additionally, their cytotoxicity was examined on different cancer cell lines and on a normal cell line, they were tracked in vitro by fluorescence detection, and their uptake was evaluated by ICP-MS measurements. [ABSTRACT FROM AUTHOR]

In DFO*, the trihydroxamate DFO is elongated with an extra hydroxamate group, exactly the same as present in DFO. Initially the in vivo stability of [ SP 89 sp Zr]Zr-DFOcyclo*-trastuzumab was compared with [ SP 89 sp Zr]Zr-DFO-trastuzumab, of which the results are depicted in Fig. [Extracted from the article]

Simple Summary: Variable domains of heavy chain only antibodies are small proteins that can be used for tumor imaging and therapy upon conjugation of functional groups. As frequently used random conjugation techniques can decrease binding to the target of interest, site-specific conjugation of these functional groups is preferred. Here, we optimized site-specific conjugation of both a chelator for binding of a radiometal and a photosensitizer to epidermal growth factor receptor (EGFR) binding VHH 7D12. We characterized this dual-labeled VHH for nuclear imaging and targeted photodynamic therapy of EGFR-expressing tumors. Variable domains of heavy chain only antibodies (VHHs) are valuable agents for application in tumor theranostics upon conjugation to both a diagnostic probe and a therapeutic compound. Here, we optimized site-specific conjugation of the chelator DTPA and the photosensitizer IRDye700DX to anti-epidermal growth factor receptor (EGFR) VHH 7D12, for applications in nuclear imaging and photodynamic therapy. 7D12 was site-specifically equipped with bimodal probe DTPA-tetrazine-IRDye700DX using the dichlorotetrazine conjugation platform. Binding, internalization and light-induced toxicity of DTPA-IRDye700DX-7D12 were determined using EGFR-overexpressing A431 cells. Finally, ex vivo biodistribution of DTPA-IRDye700DX-7D12 in A431 tumor-bearing mice was performed, and tumor homing was visualized with SPECT and fluorescence imaging. DTPA-IRDye700DX-7D12 was retrieved with a protein recovery of 43%, and a degree of labeling of 0.56. Spectral properties of the IRDye700DX were retained upon conjugation. 111In-labeled DTPA-IRDye700DX-7D12 bound specifically to A431 cells, and they were effectively killed upon illumination. DTPA-IRDye700DX-7D12 homed to A431 xenografts in vivo, and this could be visualized with both SPECT and fluorescence imaging. In conclusion, the dichlorotetrazine platform offers a feasible method for site-specific dual-labeling of VHH 7D12, retaining binding affinity and therapeutic efficacy. The flexibility of the described approach makes it easy to vary the nature of the probes for other combinations of diagnostic and therapeutic compounds. [ABSTRACT FROM AUTHOR]