Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most common cause of dementia among the elderly population. The good correlation of the density and neocortical spread of neurofibrillary tangles (NFTs) with clinical AD disease progression offers an opportunity for the early diagnosis and staging using a noninvasive imaging technique such as positron emission tomography (PET). Thus, PET imaging of NFTs not only holds promise as a diagnostic tool but also may enable the development of disease modifying therapeutics for AD. In this review, we focus on the structural diversity of tau PET tracers, the challenges related to the identification of high affinity and highly selective NFT ligands, and recent progress in the clinical development of tau PET radioligands.

Modulation of the metabotropic glutamate type 2 (mGlu2) receptor is considered a promising target for the treatment of central nervous system diseases such as schizophrenia. Here, we describe the pharmacological properties of the novel mGlu2 receptor positive allosteric modulator (PAM) 3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one (JNJ-40068782) and its radioligand

Experiments in rats and PDE10A knock-out mice indicate that (18)F-JNJ41510417 binds specifically and reversibly to PDE10A in the striatum, suggesting that this new fluorinated quinoline derivative is a promising candidate for in vivo imaging of PDE10A using PET.

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.

In this study, we have synthesized and evaluated 18 F-JNJ64349311, a tracer with high affinity for aggregated tau (inhibition constant value, 8 nM) and high ($500·) in vitro selectivity for tau over b-amyloid, in comparison with the benchmark compound 18 F-AV1451 ( 18 F-T807) in mice, rats, and a rhesus monkey. Methods: In vitro binding characteristics were determined for Alzheimer's disease, progressive supranuclear palsy, and corticobasal degeneration patient brain tissue slices using autoradiography studies. Ex vivo biodistribution studies were performed in mice. Radiometabolites were quantified in the brain and plasma of mice and in the plasma of a rhesus monkey using high-performance liquid chromatography. Dynamic small-animal PET studies were performed in rats and a rhesus monkey to evaluate tracer pharmacokinetics in the brain. Results: Mouse biodistribution studies showed moderate initial brain uptake and rapid brain washout. Radiometabolite analyses after injection of 18 F-JNJ64349311 in mice showed the presence of a polar radiometabolite in plasma, but not in the brain. Semiquantitative autoradiography studies on postmortem tissue sections of human Alzheimer's disease brains showed highly displaceable binding to tau-rich regions. No specific binding was, however, found on human progressive supranuclear palsy and corticobasal degeneration brain slices. Small-animal PET scans of Wistar rats revealed moderate initial brain uptake (SUV, ;1.5 at 1 min after injection) and rapid brain washout. Gradual bone uptake was, however, also observed. Blocking and displacement did not affect brain time-activity curves, suggesting no off-target specific binding of the tracer in the healthy rat brain. A small-animal PET scan of a rhesus monkey revealed moderate initial brain uptake (SUV, 1.9 at 1 min after injection) with a rapid washout. In the monkey, no bone uptake was detected during the 120-min scan. Conclusion: This biologic evaluation suggests that 18 F-JNJ64349311 is a promising tau PET tracer candidate, with a favorable pharmacokinetic profile, as compared with 18 F-AV1451.

In this work the thermal structure of the Iberian Peninsula is derived from magnetic data by calculating the bottom of the magnetization, assumed to be the Curie‐point depth (CPD) isotherm, which accounts for the depth at which magnetite becomes paramagnetic (580°C). Comparison of the CPD with crustal thickness maps along with a heat flow map derived from the CPD provides new insights on the lithospheric thermal regime. Within Iberia, the CPD isotherm has thickness in the range of 17 to 29 km. This isotherm is shallow (<18 km) offshore, where the lithosphere is thinner. In continental Iberia, the NW Variscan domain presents a magnetic response that is most probably linked to thickening and later extension processes during the late Variscan Orogeny, which resulted in widespread crustal melting and emplacement of granites (in the Central Iberian Arc). The signature of the CPD at the Gibraltar Arc reveals a geometry consistent with the slab roll‐back geodynamic model that shaped the western Mediterranean. In offshore areas, a broad extension of magnetized upper mantle is found. Serpentinization of the upper mantle, probably triggered in an extensional context, is proposed to account for the magnetic signal. The Atlantic margin presents up to 8 km of serpentinites, which, according to the identification of exhumed mantle, correlates with a hyperextended margin. The Mediterranean also presents generalized serpentinization up to 6 km in the Algerian Basin. Furthermore, a heat flow map and a Moho temperature map derived from the CPD are presented.

Abstract. The Spanish Central System is an intraplate mountain range that divides the Iberian Inner Plateau in two sectors – the northern Duero Basin and the Tajo Basin to the south. The topography of the area is highly variable with the Tajo Basin having an average altitude of 450–500 m and the Duero Basin having a higher average altitude of 750–800 m. The Spanish Central System is characterized by a thick-skin pop-up and pop-down configuration formed by the reactivation of Variscan structures during the Alpine orogeny. The high topography is, most probably, the response of a tectonically thickened crust that should be the response to (1) the geometry of the Moho discontinuity, (2) an imbricated crustal architecture, and/or (3) the rheological properties of the lithosphere. Shedding some light on these features is the main target of the current investigation. In this work, we present the lithospheric-scale model across this part of the Iberian Massif. We have used data from the Central Iberian Massif Deformation (CIMDEF) project, which consists of recordings of an almost-linear array of 69 short-period seismic stations, which define a 320 km long transect. We have applied the so-called global-phase seismic interferometry. The technique uses continuous recordings of global earthquakes (>120∘ epicentral distance) to extract global phases and their reverberations within the lithosphere. The processing provides an approximation of the zero-offset reflection response of a single station to a vertical source, sending (near)-vertical seismic energy. Results indeed reveal a clear thickening of the crust below the Central System, resulting, most probably, from an imbrication of the lower crust. Accordingly, the crust–mantle boundary is mapped as a relatively flat interface at approximately 10 s two-way travel time except in the Central System, where this feature deepens towards the NW reaching more than 12 s. The boundary between the upper and lower crust is well defined and is found at 5 s two-way travel time. The upper crust has a very distinctive signature depending on the region. Reflectivity at upper-mantle depths is scattered throughout the profile, located between 13 and 18 s, and probably related to the Hales discontinuity.

Advanced leads from a series of 1,2,4-triazolo[4,3-a]pyridines with mGlu2 receptor PAM activity are reported. By modification of the analogous imidazo[1,2-a]pyridine series, the newly reported leads have improved potency, in vitro ADMET, and hERG as well as good in vivo PK profile. The optimization of the series focused on improving metabolic stability while controlling lipophilicity by introducing small modifications to the scaffold substituents. Analysis of this series combined with our previously reported mGlu2 receptor PAMs showed how lipophilic ligand efficiency was improved during the course of the program. Among the best compounds, example 20 (JNJ-42153605) showed a central in vivo efficacy by inhibition of REM sleep state at a dose of 3 mg/kg po in the rat sleep-wake EEG paradigm, a phenomenon shown earlier to be mGlu2 mediated. In mice, compound 20 reversed PCP-induced hyperlocomotion with an ED₅₀ of 5.4 mg/kg sc, indicative of antipsychotic activity.