Challenges and Opportunities in Central Nervous System Drug Discovery

The development of new drugs for disorders of the central nervous system (CNS) presents unique challenges when compared with other disease areas. These include an incomplete understanding of the biology of multifaceted CNS conditions such as Alzheimer's disease, the presence of a blood–brain barrier that restricts the flow of molecules to the brain, and a lack of clinically relevant animal models in which to test new drugs. In this review, we aim to discuss some of these issues at each stage of the drug discovery process, provide examples of recent work addressing them, and consider the options available to researchers in the future

Targeting the Oxytocin System: New Pharmacotherapeutic Approaches

Deficits in social behavioral domains, such as interpersonal communication, emotion recognition, and empathy, are a characteristic symptom in several neuropsychiatric disorders, including schizophrenia and autism spectrum disorder (ASD). The neuropeptide oxytocin (OT) has emerged as a key regulator of diverse social behaviors in vertebrates and, thus, has been identified as a potential therapeutic target for improving social dysfunction. In recent years, the field of OT research has seen an explosion of scientific inquiry, producing a more comprehensive picture of oxytocinergic signaling and the pathways that regulate its release and degradation in the brain. In this review, we provide an analysis of how this information is being exploited to accelerate the discovery of novel oxytocinergic therapeutics

Radiopharmaceuticals for PET imaging of neuroinflammation - Les radiopharmaceutiques pour l’imagerie TEP de la neuroinflammation

Abstract Recently, accumulating evidence has revealed that neuroinflammation appears to be the cornerstone of many neurological diseases including stroke, multiple sclerosis, Alzheimer's disease or Parkinson's disease. Neuroinflammation causes neuronal damages by activation of numerous cells and molecular mediators in diseases involving the inflammatory process. In this article, we focus on noninvasive molecular imaging of radioligands that target inflammatory cells and molecules involved in neuroinflammation. PET is in fact one of the most promising imaging techniques to visualize and quantify neuroinflammation in vivo. We have also summarized the potential neuroinflammation imaging targets and corresponding PET radioligands. Résumé Des données scientifiques récentes et de plus en plus nombreuses ont mis en évidence le rôle central joué par le processus de neuroinflammation dans la physiopathologie de nombreuses maladies neurologiques, telles que l’accident vasculaire cérébral, la sclérose en plaques, la maladie d’Alzheimer ou encore la maladie de Parkinson. Dans ces maladies impliquant le processus inflammatoire, la neuro-inflammation cause en effet des dommages neuronaux par activation de nombreuses cellules et médiateurs moléculaires. L’imagerie par tomographie par émission de positons (TEP) apparaît comme une approche prometteuse pour visualiser et quantifier in vivo la neuro-inflammation de façon non invasive, grâce en particulier au développement de radioligands ciblant spécifiquement diverses molécules impliquées dans cette réaction inflammatoire cérébrale. Dans cette revue sont présentés les cibles moléculaires potentielles pour l’imagerie TEP de la neuro-inflammation ainsi que les médicaments radiopharmaceutiques correspondants

Reversing binding sensitivity to A147T translocator protein

The translocator protein (TSPO) is a target for the development of neuroinflammation imaging agents. Clinical translation of TSPO PET ligands, such as [11C]DPA-713, has been hampered by the presence of a common polymorphism (A147T TSPO), at which all second-generation TSPO ligands lose affinity. Little is known about what drives binding at A147T compared to WT TSPO. This study aimed to identify moieties in DPA-713, and related derivatives, that influence binding at A147T compared to WT TSPO. We found changes to the nitrogen position and number in the heterocyclic core influences affinity to WT and A147T to a similar degree. Hydrogen bonding groups in molecules with an indole core improve binding at A147T compared to WT, a strategy that generated compounds that possess up to ten-times greater affinity for A147T. These results should inform the future design of compounds that bind both A147T and WT TSPO for use in neuroinflammation imaging

Comparative evaluation of three TSPO PET radiotracers in a LPS-induced model of mild neuroinflammation in rats.

PURPOSE: Over the past 20 years, neuroinflammation (NI) has increasingly been recognised as having an important role in  many neurodegenerative diseases, including Alzheimer's disease. As such, being able to image NI non-invasively in patients is critical to monitor pathological processes and potential therapies targeting neuroinflammation. The translocator protein (TSPO) has proven a reliable NI biomarker for positron emission tomography (PET) imaging. However, if TSPO imaging in acute conditions such as stroke provides strong and reliable signals, TSPO imaging in neurodegenerative diseases has proven more challenging. Here, we report results comparing the recently developed TSPO tracers [(18)F]GE-180 and [(18)F]DPA-714 with (R)-[(11)C]PK11195 in a rodent model of subtle focal inflammation. PROCEDURES: Adult male Wistar rats were stereotactically injected with 1 μg lipopolysaccharide in the right striatum. Three days later, animals underwent a 60-min PET scan with (R)-[(11)C]PK11195 and [(18)F]GE-180 (n = 6) or [(18)F]DPA-714 (n = 6). Ten animals were scanned with either [(18)F]GE-180 (n = 5) or [(18)F]DPA-714 (n = 5) only. Kinetic analysis of PET data was performed using the simplified reference tissue model (SRTM) with a contralateral reference region or a novel data-driven input to estimate binding potential BPND. Autoradiography and immunohistochemistry were performed to confirm in vivo results. RESULTS: At 40-60 min post-injection, [(18)F]GE-180 dual-scanned animals showed a significantly increased core/contralateral uptake ratio vs. the same animals scanned with (R)-[(11)C]PK11195 (3.41 ± 1.09 vs. 2.43 ± 0.39, p = 0.03); [(18)]DPA-714 did not (2.80 ± 0.69 vs. 2.26 ± 0.41). Kinetic modelling with a contralateral reference region identified significantly higher binding potential (BPND) in the core of the LPS injection site with [(18)F]GE-180 but not with [(18)F]DPA-714 vs. (R)-[(11)C]PK11195. A cerebellar reference region and novel data-driven input to the SRTM were unable to distinguish differences in tracer BPND. CONCLUSIONS: Second-generation TSPO-PET tracers are able to accurately detect mild-level NI. In this model, [(18)F]GE-180 shows a higher core/contralateral ratio and BPND when compared to (R)-[(11)C]PK11195, while [(18)F]DPA-714 did not

The role of polycyclic frameworks in modulating P2X<inf>7</inf> receptor function

Herein we describe our recent attempts to target the P2X7 receptor for potential treatment of neurological disorders. This work focusses on different polycycles including carborane, adamantane or cubane, joined by either a cyanoguanidine or an amide linker to phenyl or isoquinoline moieties. We have demonstrated the superiority of the adamantyl moiety over other polycycles in terms of synthetic accessibility and biological (cellular) activity. We have also shown that an amide or cyanoguanidine linker can greatly alter the biological activity of compounds. This SAR study provides important insights into the types of functionality required to target the P2X7 receptor

Rapid access to N-(indol-2-yl)amides and N-(indol-3-yl)amides as unexplored pharmacophores

Published on 14 December 2016.Preparation of N-(indol-2-yl)amides and N-(indol-3-yl)amides are scarce in the scientific literature due to unstable intermediates impeding current reported syntheses. We have employed cheap and readily available substrates in the Curtius rearrangement of indole-3-carboxazide to afford N-(indol-3-yl)amides. The reaction is observed for alkyl and aryl carboxylic acids and both N-substituted or 1H-indole derivatives are tolerated. This approach was extended to the preparation of N-(indol-2-yl)amides from the corresponding indole-2-carboxazides.Tristan A. Reekie, Shane M. Wilkinson, Vivian Law, David E. Hibbs, Jennifer A. Ong and Michael Kassio

Lack of neuroinflammation in the HIV-1 transgenic rat: An [18 F]-DPA714 PET imaging study

BACKGROUND: HIV-associated neuroinflammation is believed to be a major contributing factor in the development of HIV-associated neurocognitive disorders (HAND). In this study, we used micropositron emission tomography (PET) imaging to quantify neuroinflammation in HIV-1 transgenic rat (Tg), a small animal model of HIV, known to develop neurological and behavioral problems. METHODS: Dynamic [(18)F]DPA-714 PET imaging was performed in Tg and age-matched wild-type (WT) rats in three age groups: 3-, 9-, and 16-month-old animals. As a positive control for neuroinflammation, we performed unilateral intrastriatal injection of quinolinic acid (QA) in a separate group of WT rats. To confirm our findings, we performed multiplex immunofluorescent staining for Iba1 and we measured cytokine/chemokine levels in brain lysates of Tg and WT rats at different ages. RESULTS: [(18)F]DPA-714 uptake in HIV-1 Tg rat brains was generally higher than in age-matched WT rats but this was not statistically significant in any age group. [(18)F]DPA-714 uptake in the QA-lesioned rats was significantly higher ipsilateral to the lesion compared to contralateral side indicating neuroinflammatory changes. Iba1 immunofluorescence showed no significant differences in microglial activation between the Tg and WT rats, while the QA-lesioned rats showed significant activation. Finally, cytokine/chemokine levels in brain lysates of the Tg rats and WT rats were not significantly different. CONCLUSION: Microglial activation might not be the primary mechanism for neuropathology in the HIV-1 Tg rats. Although [(18)F]DPA-714 is a good biomarker of neuroinflammation, it cannot be reliably used as an in vivo biomarker of neurodegeneration in the HIV-1 Tg rat. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-015-0390-9) contains supplementary material, which is available to authorized users