Phosphodiesterase 10A (PDE10A) plays a key role in the regulation of brain striatal signaling, and several pharmaceutical companies currently investigate PDE10A inhibitors in clinical trials for various central nervous system diseases. A PDE10A PET ligand may provide evidence that a clinical drug candidate reaches and binds to the target. Here we describe the successful discovery and initial validation of the novel radiolabeled PDE10A ligand 5,8-dimethyl-2-[2-((1-11 C-methyl)-4-phenyl-1H-imidazol-2-yl)-ethyl]-[1,2,4]triazolo [1,5-a]pyridine ( 11 C-Lu AE92686) and its tritiated analog 3 H-Lu AE92686. Methods: Initial in vitro experiments suggested Lu AE92686 as a promising radioligand, and the corresponding tritiated and 11 C-labeled compounds were synthesized. 3 H-Lu AE92686 was evaluated as a ligand for in vivo occupancy studies in mice and rats, and 11 C-Lu AE92686 was evaluated as a PET tracer candidate in cynomolgus monkeys and in humans. Results: 11 C-Lu AE92686 displayed high specificity and selectivity for PDE10A-expressing regions in the brain of cynomolgus monkeys and humans. Similar results were found in rodents using 3 H-Lu AE92686. The binding of 11 C-Lu AE92686 and 3 H-Lu AE92686 to striatum was completely and dose-dependently blocked by the structurally different PDE10A inhibitor 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (MP-10) in rodents and in monkeys. In all species, specific binding of the radioligand was seen in the striatum but not in the cerebellum, supporting the use of the cerebellum as a reference region. The binding potentials (BP ND ) of 11 C-Lu AE92686 in the striatum of both cynomolgus monkeys and humans were evaluated by the simplified reference tissue model with the cerebellum as the reference tissue, and BP ND was found to be high and reproducible-that is, BP ND s were 6.5 ± 0.3 (n 5 3) and 7.5 ± 1.0 (n 5 12) in monkeys and humans, respectively. Conclusion: Rodent, monkey, and human tests of labeled Lu AE92686 suggest that 11 C-Lu AE92686 has great potential as a human PET tracer for the PDE10A enzyme.Key Words: 11 C; 3 H; PET; PDE10A; brain imaging; Lu AE92686 J Nucl Med 2014; 55:1513 55: -1518 55: DOI: 10.2967 Phosphodi esterase 10A (PDE10A) is predominantly expressed in medium spiny neurons and plays a key role in striatal signaling. During the past 10 y, large efforts have been made to develop PDE10A inhibitors for the treatment of schizophrenia (1-3). Preclinical evidence in several animal models suggests that PDE10A inhibitors can improve positive, negative, and cognitive symptoms of schizophrenia, and current clinical trials evaluate PDE10A inhibitors for the treatment of schizophrenia (4). Noninvasive imaging techniques such as PET may be useful for the clinical development of PDE10A inhibitors, because they may provide comparative data on the expression of the enzyme in healthy individuals and in individuals with brain disorders. Furthermore, a PDE10A PET ligand can be used to provide evidence that a clinical drug candidate reaches and bind...

This study investigates the occurrence of valveless pumping in a fluid-filled system consisting of two open tanks connected by an elastic tube. We show that directional flow can be achieved by introducing a periodic pinching applied at an asymmetrical location along the tube, and that the flow direction depends on the pumping frequency. We propose a relation between wave propagation velocity, tube length, and resonance frequencies associated with shifts in the pumping direction using numerical simulations. The eigenfrequencies of the system are estimated from the linearized system, and we show that these eigenfrequencies constitute the resonance frequencies and the horizontal slope frequencies of the system; "horizontal slope frequency" being a new concept. A simple model is suggested, explaining the effect of the gravity driven part of the oscillation observed in response to the tank and tube diameter changes. Results are partly compared with experimental findings.

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Brodalumab is a fully human monoclonal antibody targeting the IL‐17 receptor A leading to an inhibition of the biological effect of IL‐17A, IL‐17F, IL‐17A/F heterodimer, IL‐17C and IL‐17E isoforms. It has shown to be efficacious in the treatment of moderate to severe plaque psoriasis (210 mg administered subcutaneously at weeks 0, 1 and 2 followed by 210 mg every 2 weeks [Q2W+1]). A population pharmacokinetic model based on psoriasis patients only from six clinical trials was developed to describe the pharmacokinetics and identify sources of variability. In patients with psoriasis, Brodalumab exhibits non‐linear pharmacokinetics due to target‐mediated drug disposition resulting in concentration‐dependent clearance. The pharmacokinetics was best described by a two‐compartment model with linear absorption and combined linear and Michaelis‐Menten elimination. The subcutaneous bioavailability of Brodalumab was 55%, absorption rate was 0.30 day−1, and body‐weight was found to affect the volume of distribution and clearance. For a reference patient with plaque psoriasis (body‐weight of 90 kg), the estimates were 0.16 L/d for linear serum clearance, 6.1 mg/d for the maximum non‐linear clearance rate, and 4.7 and 2.4 L for central and peripheral volume of distribution, respectively. For the approved dosing regimen, time to maximum concentration was 4 days and 90% of steady‐state was achieved after 10 weeks for a reference patient. Following last dose at steady‐state, 90% of the population of reference patients will reach serum concentrations below lower limit of quantification after 45 days.

Tralokinumab is the first biologic therapy for moderate‐to‐severe atopic dermatitis (AD) that specifically neutralizes interleukin‐13 activity, a key driver of AD signs and symptoms. Tralokinumab is a human immunoglobulin G4 monoclonal antibody administered subcutaneously every 2 weeks (with possibility of maintenance dosing every 4 weeks). This population pharmacokinetic (PK) analysis aimed to identify sources of PK variability and relevant predictors of tralokinumab exposure in adults with moderate to severe AD. Nonlinear mixed‐effect modeling, including covariate analysis, was used on a data set including 2561 subjects (AD, asthma, healthy) from 10 clinical trials. A 2‐compartment model with first‐order absorption and elimination adequately described the tralokinumab PK. Body weight was identified as a relevant predictor of tralokinumab exposure; other covariates including age, sex, race, ethnicity, disease type, AD severity, and renal and hepatic impairment were not. For body weight, the difference in exposure between the upper‐ and lower‐weight quartiles in patients with AD was <2‐fold, supporting the appropriateness of flat dosing (300 mg). Given the reduced exposure associated with higher body weight, coupled with the reduced exposure provided by dosing every 4 weeks, it is uncertain whether higher‐weight patients will achieve sufficient exposure to maintain efficacy if dosed every 4 weeks instead of the standard every 2 weeks.