Synthesis and automated fluorine-18 radiolabeling of new PSMA-617 derivatives with a CuAAC radiosynthetic approach

In the last decade, the development of new radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research, especially focusing on the prostate-specific membrane antigen (PSMA), an antigen which is upregulated in prostate, as well as in other tumor cells. A large variety of PSMA ligands have been radiolabeled, to date. Among the various derivatives, PSMA-617 resulted to be one of the most interesting in terms of interaction with the antigen and clinical properties, and its lutetium-177 labeled version has recently been approved by regulatory agencies for therapeutic purposes. For this reasons, the radiolabeling with fluorine-18 of a PSMA-617 derivative might be of interest. Beside other methodologies to radiolabel macromolecules with fluorine-18, the “click-chemistry” approach resulted to be very useful, and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is considered one of most efficient and reliable. This paper proposes the synthesis of a suitable precursor for the radiolabeling with fluorine-18 of a new PSMA-617 derivative. The whole radiosynthetic procedure has been fully automated, and the final product, which proved to be stable in plasma, has been obtained with radiochemical yield and purity suitable for subsequent preclinical studies.     

Insights into the pathogenesis of ATP1A1‐related CMT disease using patient‐specific iPSCs

The development of patient‐specific induced pluripotent stem cells (iPSCs) offered interesting insights in modeling the pathogenesis of Charcot‐Marie‐Tooth (CMT) disease and thus we decided to explore the phenotypes of iPSCs derived from a single CMT patient carrying a mutant ATP1A1 allele (p.Pro600Ala). iPSCs clones generated from CMT and control fibroblasts, were induced to differentiate into neural precursors and then into post‐mitotic neurons. Control iPSCs differentiated into neuronal precursors and then into post‐mitotic neurons within 6‐8 days. On the contrary, the differentiation of CMT iPSCs was clearly defective. Electrophysiological properties confirmed that post‐mitotic neurons were less mature compared to the normal counterpart. The impairment of in vitro differentiation of CMT iPSCs only concerned with the neuronal pathway, because they were able to differentiate into mesendodermal cells and other ectodermal derivatives. ATP1A1 was undetectable in the few neuronal cells derived from CMT iPSCs. ATP1A1 gene mutation (p.Pro600Ala), responsible for a form of axonal CMT disease, is associated in vitro with a dramatic alteration of the differentiation of patient‐derived iPSCs into post‐mitotic neurons. Thus, the defect in neuronal cell development might lead in vivo to a decreased number of mature neurons in ATP1A1‐CMT disease.     

The efficacy of interventions aimed at improving post-partum bonding: A review of interventions addressing parent-infant bonding in healthy and at risk populations

Parent-infant bonding during the postpartum period allows babies to start establishing a relationship with their parents from birth, and it also plays an important role in child development. As the failure to building a close and positive bond is typically associated with poorer neuropsychological, behavioural, emotional, and social development from infancy to adulthood, early interventions that support parent-infant bonding seem particularly important. This review aims to determine and describe the effectiveness of interventions addressing parent-infant bonding during the postpartum period. Papers that were published between 2007 and 2017, written in English, and focused on an intervention aimed at improving postpartum parent-infant bonding were identified and assessed, concerning their eligibility for inclusion; thirteen such interventions met inclusion criteria and analysed. These studies addressed parent-infant bonding interventions, both in normative and at-risk situations, relative to both parents and their babies, and evaluated the impact of different strategies, such as educational and behavioural programs, psychosocial interventions, programs providing instruction in specific techniques, and interventions based on neurostimulation techniques. The heterogeneous methodologies employed by the various studies failed to enable us to pursue deep comparative analyses across our findings; this reflects a limitation that must be considered in further research aimed at implementing and evaluating future interventions.     

Alterations in Carotid Parameters in ApoE–/– Mice Treated with a High-Fat Diet: A Micro-ultrasound Analysis

Information on the common carotid artery and cerebral microcirculation can be obtained by micro-ultrasound (µUS). The aim of the study described here was to investigate high-fat diet-induced alterations in vascular parameters in ApoE–/– mice. Twenty-two ApoE–/– male mice were examined by µUS and divided into the standard diet (ApoE–/–_SD) and high-fat diet (ApoE–/–_HF) groups. The µUS examination was repeated after 4 mo (T₁). Carotid stiffness, reflection magnitude and reflection index were measured; the amplitudes of the first (W₁) and second (W₂) local maxima, the local minimum (W_b) and the reflection index (RI_WIA?=?W_b/W₁) were assessed with wave intensity analysis. At T₁, ApoE–/–_HF mice had increased carotid stiffness (1.48 [0.36] vs. 1.88 [0.51]) and reflection magnitude (0.89 [0.07] vs. 0.94 [0.07]) values. Longitudinal comparisons highlighted increases in carotid stiffness for ApoE–/–_HF mice (from 1.37 [0.25] to 1.88 [0.51] m/s) but not for ApoE–/–_SD mice (from 1.40 [0.62] to 1.48 [0.36] m/s). ApoE–/–_HF mice exhibited carotid artery stiffening and increased wave reflections.     

Effects of Mu-Opiate Receptor Gene Polymorphism rs1799971 (A118G) on the Antidepressant and Dissociation Responses in Esketamine Nasal Spray Clinical Trials

BackgroundAt ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR–gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses.MethodsParticipants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery–Åsberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25.ResultsIn the esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected.ConclusionsVariation in rs1799971 (A118G) did not affect the antidepressant response to esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect.Trial Registration{"type":"clinical-trial","attrs":{"text":"NCT02417064","term_id":"NCT02417064"}}NCT02417064 and {"type":"clinical-trial","attrs":{"text":"NCT02418585","term_id":"NCT02418585"}}NCT02418585; www.clinicaltrials.gov