Tozadenant or Preladenant or Vipadenant

Tozadenant (4-hydroxy- N -(4-methoxy-7-morpholinobenzo[ d ]thiazol-2-yl)-4-methylpiperidine-1-carboxamide) is a highly selective adenosine A2A receptor (A2A R) antagonist and a promising lead structure for the development of A2A R-selective positron emission tomography (PET) probes. Although several 18 F-labelled tozadenant derivatives showed favorable in vitro properties, recent in vivo PET studies observed poor brain penetration and lower specific binding than anticipated from the in vitro data. While these findings might be attributable to the structural modification associated with 18 F-labelling, they could also reflect inherent properties of the parent compound...

Immunotherapy is a promising cancer treatment strategy. In contrast, PD-1/PD-L1 inhibitors are associated with low response rates and are only useful in a small group of cancer patients. A combination of treatments may be effective for overcoming this clinical issue. Preladenant is an adenosine receptor inhibitor that can block the adenosine pathway and improve the tumor microenvironment (TME), thereby enhancing the immunotherapeutic effect of PD-1 inhibitors. However, its poor water solubility and low targeting limit its clinical applications...

The clinical impact of therapeutic interventions in Parkinson's disease is often measured as a reduction in OFF-time when the beneficial effects of the standard-of-care L-DOPA formulations wanes off. We investigated the pharmacodynamic interactions of augmentation therapy to standard-of-care using a quantitative systems pharmacology (QSP) model of the basal ganglia motor circuit, essentially a computer model of neuronal firing in the different subregions with anatomically informed connectivity, cell-specific expression of 17 different G-protein coupled receptors and corresponding coupling to voltage-gated ion channel effector proteins based on experimentally observed intracellular signaling...

Compound-mediated locomotion changes, conducted via open field infrared photobeam breaks, are an important common component of neurological assessments conducted in safety pharmacology studies. In addition to open field locomotor activity assessments, activity data (derived from changes in signal strength) from cardiovascular (CV) telemetry studies can also be an alternative method potentially used to assess locomotor effects. However, comparisons of these two methods have not been extensively characterized...

The cerebral expression of the A2A adenosine receptor (A2A AR) is altered in neurodegenerative diseases such as Parkinson's (PD) and Huntington's (HD) diseases, making these receptors an attractive diagnostic and therapeutic target. We aimed to further investigate the pharmacokinetic properties in the brain of our recently developed A2A AR-specific antagonist radiotracer [18 F]FLUDA. For this purpose, we retrospectively analysed dynamic PET studies of healthy mice and rotenone-treated mice, and conducted dynamic PET studies with healthy pigs...

BACKGROUND: Coffee intake can decrease the risk for Parkinson's disease (PD). Its beneficial effects are allegedly mediated by caffeine through adenosine A2A receptor (A2A R) antagonist action. OBJECTIVE: We aimed to calculate occupancy rates of striatal A2A Rs by caffeine after coffee intake in PD. METHODS: Five patients with PD underwent 11 C-preladenant positron emission tomography scanning at baseline and after intake of coffee containing 129...

Adenosine is an endogenous purine-based nucleoside expressed nearly in all body tissues. It regulates various body functions by activating four G-protein coupled receptors, A1 , A2A , A2B , and A3 . These receptors are widely acknowledged as drug targets for treating different neurological, metabolic, and inflammatory diseases. Although numerous adenosine receptor inhibitors have been developed worldwide, achieving target selectivity is still a big hurdle in drug development. However, the identification of specific radioligands-based affinity assay, fluorescent ligands, and MS-based ligand assay have contributed to the development of selective and potent adenosine ligands...

OBJECTIVE: To evaluate the reproducibility of cerebral adenosine A2A receptor (A2A R) quantification using [11 C]preladenant ([11 C]PLN) and PET in a test-retest study. METHODS: Eight healthy male volunteers were enrolled. Dynamic 90 min PET scans were performed twice at the same time of the day to avoid the effect of diurnal variation. Subjects refrained from caffeine from 12 h prior to scanning, and serum caffeine was measured before radioligand injection. Arterial blood was sampled repeatedly during scanning and the fraction of the parent compound in plasma was determined...

Immunometabolic modulation offers new opportunities to treat cancers as it is highly associated with cancer progression and immunosuppressive microenvironment. However, traditional regimens using nonselective small-molecule immunomodulators lead to the off-target adverse effects and insufficient therapeutic outcomes. Herein a second near-infrared (NIR-II) photothermally activatable semiconducting polymeric nanoantagonist (ASPA) for synergistic photothermal immunometabolic therapy of cancer is reported. ASPA backbone is obtained by conjugating vipadenant, an antagonist to adenosine A2A receptor, onto NIR-II light-absorbing semiconducting polymer via an azo-based thermolabile linker...

Several lines of evidence have strongly implicated neuroinflammation in Parkinson's disease (PD) progression and l-dopa-induced dyskinesia. The present study investigated whether early subchronic pretreatment with the serotonin 5-HT1A/1B receptor agonist eltoprazine plus the adenosine A2A receptor antagonist preladenant counteracted l-dopa-induced abnormal involuntary movements (AIMs, index of dyskinesia), and neuroinflammation, in unilateral 6-hydroxydopamine(6-OHDA)-lesion rat model of PD. The immunoreactivity of glial-fibrillary-acidic-protein (GFAP), and the colocalization of ionized calcium-binding-adaptor-molecule-1(IBA-1), with interleukin (IL)-1β, tumor-necrosis-factor-α (TNF-α) and IL-10 were evaluated in denervated caudate-putamen (CPu) and substantia nigra pars-compacta (SNc)...

The adenosine A2A receptor (A2A R) represents a potential therapeutic target for neurodegenerative diseases. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor changes of receptor density and/or occupancy during the A2A R-tailored therapy, we designed a library of fluorinated analogs based on a recently published lead compound ( PPY ). Among those, the highly affine 4-fluorobenzyl derivate ( PPY1 ; K i ( h A2A R) = 5.3 nM) and the 2-fluorobenzyl derivate ( PPY2 ; K i ( h A2A R) = 2...

With the aim to obtain potent adenosine A2A receptor (A2A R) ligands, a series of eighteen derivatives of 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide (SYN-115, Tozadenant) were designed and synthesized. The target compounds were obtained by a chemical building block principle that involved reaction of the appropriate aminobenzothiazole phenyl carbamates with either commercially available or readily synthesized functionalized piperidines. Their affinity and subtype selectivity with regard to human adenosine A1 -and A2A receptors were determined using radioligand binding assays...

The adenosine A2A receptor (A2A R) has emerged as a potential non-dopaminergic target for the treatment of Parkinson's disease and, thus, the non-invasive imaging with positron emission tomography (PET) is of utmost importance to monitor the receptor expression and occupancy during an A2A R-tailored therapy. Aiming at the development of a PET radiotracer, we herein report the design of a series of novel fluorinated analogs ( TOZ1 - TOZ7 ) based on the structure of the A2A R antagonist tozadenant , and the preclinical evaluation of [18 F] TOZ1 ...

Laboratory and clinical experience have pointed to the value of targeting motor pathways emerging from the striatum to treat problems arising in advanced Parkinson's disease (PD). These pathways are selectively populated with a subtype of adenosine binding sites (A2A receptors) that offer a target for improving PD symptomatology. Several compounds were developed that possess high selectivity and potency for blocking this receptor. Three of these compounds - istradefylline, preladenant, and tozadenant - were chosen for clinical development programs that culminated in Phase 3 multicenter randomized clinical trials...

Parkinson's Disease (PD) is a neurodegenerative disease involving degeneration of dopaminergic neurons of the nigrostriatal pathways. Over the past decades, most of the medications for the treatment of PD patients have been used to modulate dopamine concentrations in the basal ganglia. This includes levodopa and its inhibitory metabolizing enzymes. In addition to modulating dopamine concentrations in the brain, there are D2-like dopamine receptor agonists that mimic the action of dopamine to compensate for the deficit in dopamine found in PD patients...

Among the class A G protein-coupled receptors (GPCR), the human adenosine A2A receptor (hA2AAR) represents an attractive drug target and has been the subject of intensive medicinal chemistry research during the last forty years. However, translation of A2AAR ligands into the clinic has proved challenging. A better understanding of the molecular mechanisms underlying the A2AAR-specific pharmacology, under either physiological or pathological conditions, could promote the development of more efficacious therapies...

Tozadenant is one of the selective adenosine A2a receptor antagonists with a potential to be a new Parkinson's disease (PD) therapeutic drug. In this study, a liquid chromatography-mass spectrometry based bioanalytical method was qualified and applied for the quantitative analysis of tozadenant in rat plasma. A good calibration curve was observed in the range from 1.01 to 2200 ng/mL for tozadenant using a quadratic regression. In vitro and preclinical in vivo pharmacokinetic (PK) properties of tozadenant were studied through the developed bioanalytical methods, and human PK profiles were predicted using physiologically based pharmacokinetic (PBPK) modeling based on these values...

A simple and sensitive liquid chromatography⁻quadrupole-time-of-flight⁻mass spectrometric (LC-QTOF-MS) assay has been developed for the evaluation of drug metabolism and pharmacokinetics (PK) properties of vipadenant in rat, a selective A2a receptor antagonist as one of the novel immune checkpoint inhibitors. A simple protein precipitation method using acetonitrile was used for the sample preparation and the pre-treated samples were separated by a reverse-phase C18 column. The calibration curve was evaluated in the range of 3...

Istradefylline, an adenosine A2A receptor (A2A R) antagonist, is effective as an adjunct to levodopa and can alleviate "off" time and motor symptoms in patients with Parkinson's disease (PD). The present study aimed to calculate occupancy rates of A2A Rs by administrating istradefylline 20 mg or 40 mg, which is the currently approved dose for PD in Japan. Additionally, A2A R availability was compared between patients with PD and healthy controls. Ten patients with PD under levodopa therapy and six age-matched healthy controls were included...

In the past decades, many efforts were undertaken to develop ligands for the adenosine receptors, with the purpose to individuate agonists and antagonists affinity and selectivity for each subtypes, namely A1, A2A, A2B, and A3. These intense studies allowed a deeper knowledge of the nature and, moreover, of the pathophysiological roles of all the adenosine receptor subtypes. In particular, the involvement of the A2A adenosine receptor subtype in some physiological mechanisms in the brain, that could be related to important diseases such as the Parkinson's disease, encouraged the research in this field...