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Targeting the prostate-specific membrane antigen (PSMA) with radiopharmaceuticals for imaging and/or therapy has demonstrated significant advancement in the management of prostate cancer patients. However, PSMA targeting remains unsuccessful in prostate cancers with low expression of PSMA, which account for 15% of cases. The neurotensin receptor-1 (NTS 1 ) has been highlighted as a suitable oncotarget for imaging and therapy of PSMA-negative prostate cancer lesions. Therefore, heterobivalent probes targeting both PSMA and NTS 1 could improve the prostate cancer management. Herein, we report the development of a branched hybrid probe ( JMV 7489 ) designed to target PSMA and/or NTS 1 bearing relevant pharmacophores and DOTA as the chelating agent. The new ligand was synthesized with a hybrid approach, which includes both syntheses in batch and in the solid phase. Saturation binding experiments were next performed on HT-29 and PC3-PIP cells to derive K d and B max values. On the PC3-PIP cells, [ 68 Ga]Ga- JMV 7489 displayed good affinity towards PSMA ( K d = 53 ± 17 nM; B max = 1393 ± 29 fmol/10 6 cells) in the same range as the corresponding reference monomer. A lower affinity value towards NTS 1 was depicted ( K d = 157 ± 71 nM; B max = 241 ± 42 fmol/10 6 cells on PC3-PIP cells; K d = 246 ± 1 nM; B max = 151 ± 44 fmol/10 6 cells on HT-29 cells) and, surprisingly, it was also the case for the corresponding monomer [ 68 Ga]Ga- JMV 7089 . These results indicate that the DOTA macrocycle and the linker are critical elements to design heterobivalent probes targeting PSMA and NTS 1 with high affinity towards NTS 1 ., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Varietal thiols have an impact on the overall aroma of many white, rosé, and red wines and beers. They originate from the metabolism of non-odorant aroma precursors by yeast during the fermentation step, via an intrinsic enzyme, the carbon-sulfur β-lyase (CSL, EC 4.4.1.13). However, this metabolism is directly dependent upon efficient internalization of aroma precursors and intracellular CSL activity. Consequently, the overall CSL activity converts on average only 1% of the total precursors available. To improve the conversion of thiol precursors during winemaking or brewing, we investigated the possibility of using an exogenous CSL enzyme from Lactobacillus delbrueckii subsp. bulgaricus produced in Escherichia coli . We first implemented a reliable spectrophotometric method to monitor its activity on different related aroma precursors and studied its activity in the presence of various competing analogues and at different pH values. This study allowed us to highlight the parameters to define CSL activity and structural insights for the recognition of the substrate, which pave the way for the use of exogenous CSL for the release of aromas in beer and wine.

Chronic pain is one of the most critical health issues worldwide. Despite considerable efforts to find therapeutic alternatives, opioid drugs remain the gold standard for pain management. The administration of μ-opioid receptor (MOR) agonists is associated with detrimental and limiting adverse effects. Overall, these adverse effects strongly overshadow the effectiveness of opioid therapy. In this context, the development of neurotensin (NT) ligands has shown to be a promising approach for the management of chronic and acute pain. NT exerts its opioid-independent analgesic effects through the binding of two G protein-coupled receptors (GPCRs), NTS1 and NTS2. In the last decades, modified NT analogues have been proven to provide potent analgesia in vivo. However, selective NTS1 and nonselective NTS1/NTS2 ligands cause antinociception associated with hypothermia and hypotension, whereas selective NTS2 ligands induce analgesia without altering the body temperature and blood pressure. In light of this, various structure-activity relationship (SAR) studies provided findings addressing the binding affinity of ligands towards NTS2. Herein, we comprehensively review peptide-based NTS2-selective ligands as a robust alternative for future pain management. Particular emphasis is placed on SAR studies governing the desired selectivity and associated in vivo results., (© 2022 The Authors. Journal of Peptide Science published by European Peptide Society and John Wiley & Sons Ltd.)

The imaging of Prostate-Specific Membrane Antigen (PSMA) is now widely used at the initial staging of prostate cancers in patients with a high metastatic risk. However, its ability to detect low-grade tumor lesions is not optimal., Methods: First, we prospectively performed neurotensin receptor-1 (NTS 1 ) IHC in a series of patients receiving both [ 68 Ga]Ga-PSMA-617 and [ 68 Ga]Ga-RM2 before prostatectomy. In this series, PSMA and GRP-R IHC were also available (n = 16). Next, we aimed at confirming the PSMA/GRP-R/NTS 1 expression profile by retrospective autoradiography (n = 46) using a specific radiopharmaceuticals study and also aimed to decipher the expression of less-investigated targets such as NTS 2 , SST 2 and CXCR4., Results: In the IHC study, all samples with negative PSMA staining (two patients with ISUP 2 and one with ISUP 3) were strongly positive for NTS 1 staining. No samples were negative for all three stains-for PSMA, GRP-R or NTS 1 . In the autoradiography study, binding of [ 111 In]In-PSMA-617 was high in all ISUP groups. However, some samples did not bind or bound weakly to [ 111 In]In-PSMA-617 (9%). In these cases, binding of [ 111 n]In-JMV 6659 and [ 111 In]In-JMV 7488 towards NTS 1 and NTS 2 was high., Conclusions: Targeting PSMA and NTS 1 /NTS 2 could allow for the detection of all intraprostatic lesions.

Neurotensin receptor 2 (NTS 2 ) is a well-known mediator of central opioid-independent analgesia. Seminal studies have highlighted NTS 2 overexpression in a variety of tumors including prostate cancer, pancreas adenocarcinoma, and breast cancer. Herein, we describe the first radiometalated neurotensin analogue targeting NTS 2 . JMV 7488 (DOTA-(βAla) 2 -Lys-Lys-Pro-(D)Trp-Ile-TMSAla-OH) was prepared using solid-phase peptide synthesis, then purified, radiolabeled with 68 Ga and 111 In, and investigated in vitro on HT-29 cells and MCF-7 cells, respectively, and in vivo on HT-29 xenografts. [ 68 Ga]Ga-JMV 7488 and [ 111 In]In-JMV 7488 were quite hydrophilic (logD 7.4 = -3.1 ± 0.2 and -2.7 ± 0.2, respectively, p < 0.0001). Saturation binding studies showed good affinity toward NTS 2 ( K D = 38 ± 17 nM for [ 68 Ga]Ga-JMV 7488 on HT-29 and 36 ± 10 nM on MCF-7 cells; K D = 36 ± 4 nM for [ 111 In]In-JMV 7488 on HT-29 and 46 ± 1 nM on MCF-7 cells) and good selectivity (no NTS 1 binding up to 500 nM). On cell-based evaluation, [ 68 Ga]Ga-JMV 7488 and [ 111 In]In-JMV 7488 showed high and fast NTS 2 -mediated internalization of 24 ± 5 and 25 ± 11% at 1 h for [ 111 In]In-JMV 7488, respectively, along with low NTS 2 -membrane binding (<8%). Efflux was as high as 66 ± 9% at 45 min for [ 68 Ga]Ga-JMV 7488 on HT-29 and increased for [ 111 In]In-JMV 7488 up to 73 ± 16% on HT-29 and 78 ± 9% on MCF-7 cells at 2 h. Maximum intracellular calcium mobilization of JMV 7488 was 91 ± 11% to that of levocabastine, a known NTS 2 agonist on HT-29 cells demonstrating the agonist behavior of JMV 7488. In nude mice bearing HT-29 xenograft, [ 68 Ga]Ga-JMV 7488 showed a moderate but promising significant tumor uptake in biodistribution studies that competes well with other nonmetalated radiotracers targeting NTS 2 . Significant uptake was also depicted in lungs. Interestingly, mice prostate also demonstrated [ 68 Ga]Ga-JMV 7488 uptake although the mechanism was not NTS 2 -mediated., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

Synthesis of fluorescent P-hydroxybinaphtylphosphole-oxide or -sulfide was achieved by trapping a binaphtyl dianion with methyl dichlorophosphite or P-(N,N-diethylamino)dichlorophosphine, followed by oxidation or sulfuration of the P-center. After saponification or acid hydrolysis, the P-hydroxyphospholes were coupled to peptides using the coupling agent BOP, under the conditions required for the synthesis in solution or on a solid support. This new method was illustrated by the labeling of the JMV2959, a potent antagonist of the Growth Hormone Secretagogue Receptor type 1a (GHS-R1a). The labeled conjugates were used to characterize GHSR ligands by competition assays, based on Fluorescence Resonance Energy Transfer (FRET). Such P-hydroxyphosphole-oxide or -sulfide constitute a promising new class of compact fluorophores with large Stokes shift, for labeling biomolecules by grafting through the phosphorus atom., (© 2022 Wiley-VCH GmbH.)

The endogenous tridecapeptide neurotensin (NT) has emerged as an important inhibitory modulator of pain transmission, exerting its analgesic action through the activation of the G protein-coupled receptors, NTS1 and NTS2. Whereas both NT receptors mediate the analgesic effects of NT, NTS1 activation also produces hypotension and hypothermia, which may represent obstacles for the development of new pain medications. In the present study, we implemented various chemical strategies to improve the metabolic stability of the biologically active fragment NT(8-13) and assessed their NTS1/NTS2 relative binding affinities. We then determined their ability to reduce the nociceptive behaviors in acute, tonic, and chronic pain models and to modulate blood pressure and body temperature. To this end, we synthesized a series of NT(8-13) analogs carrying a reduced amide bond at Lys 8 -Lys 9 and harboring site-selective modifications with unnatural amino acids, such as silaproline (Sip) and trimethylsilylalanine (TMSAla). Incorporation of Sip and TMSAla respectively in positions 10 and 13 of NT(8-13) combined with the Lys 8 -Lys 9 reduced amine bond (JMV5296) greatly prolonged the plasma half-life time over 20 h. These modifications also led to a 25-fold peptide selectivity toward NTS2. More importantly, central delivery of JMV5296 was able to induce a strong antinociceptive effect in acute (tail-flick), tonic (formalin), and chronic inflammatory (CFA) pain models without inducing hypothermia. Altogether, these results demonstrate that the chemically-modified NT(8-13) analog JMV5296 exhibits a better therapeutic profile and may thus represent a promising avenue to guide the development of new stable NT agonists and improve pain management., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Volatile thiols are very strong-smelling molecules that can impact the aroma of numerous beverages. Several thiols and thiol precursors have been reported previously in different plants used as raw material for beverages, some of which are fermented. We focused on thiols in beverages and their release mechanisms from precursors during processing. Volatile thiols in beverages can be classified aslow molecular weight volatile thiols (e.g. H 2 S, methanethiol) which impact the smell negatively, and volatile thiols with higher boiling points that contribute positively to the aroma profile. The first part of this review is devoted to volatile thiols, without considering small malodorous molecules. The second part deals with thiol precursors and the different release mechanisms induced by processing (e.g. extraction, roasting or fermentation) and by the growing methods (e.g. viticulture), which can impact on amounts of thiols and their precursors., (Copyright © 2020 Elsevier Ltd. All rights reserved.)