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The objective of this study was to assess the effect of secukinumab, a monoclonal antibody that inhibits interleukin (IL)-17A, on number of new active brain magnetic resonance imaging (MRI) lesions in subjects with relapsing-remitting multiple sclerosis (MS). Subjects ( N  = 73) were randomized 1:1 to secukinumab 10 mg/kg or placebo by intravenous infusion at weeks 0, 2, 4, 8, 12, 16, and 20. MRI scans were obtained within 30 days prior to randomization, on a monthly basis during the treatment period, and at study completion. The primary endpoint was the cumulative number of combined unique active lesions (CUAL) observed on brain MRI scans from week 4 to week 24. Compared with placebo, secukinumab non-significantly reduced the number of CUAL observed on 4-weekly MRI from week 4 to 24 (primary endpoint) by 49 % (95 % CI −10 to 77 %; P  = 0.087) and significantly reduced the number of cumulative new gadolinium-enhancing T1 lesions by 67 % (31–84 %, P  = 0.003). CUAL reductions were progressively greater from week 4 (1 %) to week 16 (49 %) and persisted until end-study (50 %). There were no serious adverse events; the adverse event rate was comparable to placebo (53 versus 49 %), although mild-to-moderate infection was somewhat more frequent (37 versus 23 %). This proof-of-concept study provides the first evidence that blocking IL-17A with an antibody may reduce MRI lesion activity in MS. Further studies are needed to confirm this finding and determine the magnitude of effect.

An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.

Background: The efficacy and safety of bimekizumab (BKZ), an inhibitor of interleukin (IL)-17F in addition to IL-17A, has been established in axial spondyloarthritis (axSpA). Early assessment of new bone formation is possible using 18F-fluoride positron emission tomography-computerised tomography (PET-CT) imaging to quantitatively monitor osteoblastic activity. Objectives: This exploratory study, initiated before phase IIb/III studies, assessed the efficacy and safety of BKZ in patients with radiographic (r-)axSpA and its effect on new bone formation. Design: Patients were randomised 2:1 to BKZ 160 mg every 2 weeks (Q2W; Weeks 0–10) then 320 mg Q4W (Weeks 12–44), or the reference drug: certolizumab pegol (CZP) 400 mg Q2W (Weeks 0–4), then 200 mg Q2W (Weeks 6–10), 400 mg Q4W (Weeks 12–44). Methods: Primary (Axial Spondyloarthritis Disease Activity Score (ASDAS) change from baseline (CfB)) and secondary endpoints (ASDAS-ID, ASDAS-MI) were assessed at Week 12. PET-positive axSpA lesion counts and osteoblastic activity quantification (mean SUVauc) were performed at baseline and Weeks 12 and 48 in the sacroiliac joints and spine (PET-CT substudy; not powered to evaluate differences). Results: In total, 76 patients were randomised; 26/76 entered the PET-CT substudy. At Week 12, the mean ASDAS CfB with BKZ was −2.1 (CZP: −1.8); ASDAS-ID and ASDAS-MI were achieved by 23.9% (11/46) (CZP: 20.8% (5/24)) and 60.9% (28/46) (CZP: 45.8% (11/24)) patients. Across treatments, clinical efficacy was maintained or increased further at Week 48. In the PET-CT substudy, the total number of PET-positive axSpA lesions and mean SUVauc were substantially reduced from baseline at Week 12 with BKZ and CZP, with reductions maintained or further reduced at Week 48. Treatments were well tolerated with no new safety signals. Conclusion: Dual inhibition of IL-17A and IL-17F with BKZ resulted in improved clinical outcomes and reduced osteoblastic activity in patients with r-axSpA, suggesting the potential of BKZ to reduce disease activity and new bone formation within 12 weeks of treatment. CZP findings were consistent with previous data. No new safety signals were identified. Trial registration: ClinicalTrials.gov, NCT03215277 (https://clinicaltrials.gov/study/NCT03215277).

BackgroundAntiepileptic drugs, levetiracetam (LEV) and brivaracetam (BRV), bind to synaptic vesicle glycoprotein 2A (SV2A). In their anti-seizure activity, speed of brain entry may be an important factor. BRV showed faster entry into the human and non-human primate brain, based on more rapid displacement of SV2A tracer 11C-UCB-J. To extract additional information from previous human studies, we developed a nonlinear model that accounted for drug entry into the brain and binding to SV2A using brain 11C-UCB-J positron emission tomography (PET) data and the time-varying plasma drug concentration, to assess the kinetic parameter K1 (brain entry rate) of the drugs.MethodDisplacement (LEV or BRV p.i. 60 min post-tracer injection) and post-dose scans were conducted in five healthy subjects. Blood samples were collected for measurement of drug concentration and the tracer arterial input function. Fitting of nonlinear differential equations was applied simultaneously to time-activity curves (TACs) from displacement and post-dose scans to estimate 5 parameters: K1 (drug), K1(11C-UCB-J, displacement), K1(11C-UCB-J, post-dose), free fraction of 11C-UCB-J in brain (fND(11C-UCB-J)), and distribution volume of 11C-UCB-J (VT(UCB-J)). Other parameters (KD(drug), KD(11C-UCB-J), fP(drug), fP(11C-UCB-J, displacement), fP(11C-UCB-J, post-dose), fND(drug), koff(drug), koff(11C-UCB-J)) were fixed to literature or measured values.ResultsThe proposed model described well the TACs in all subjects; however, estimates of drug K1 were unstable in comparison with 11C-UCB-J K1 estimation. To provide a conservative estimate of the relative speed of brain entry for BRV vs. LEV, we determined a lower bound on the ratio BRV K1/LEV K1, by finding the lowest BRV K1 or highest LEV K1 that were statistically consistent with the data. Specifically, we used the F test to compare the residual sum of squares with fixed BRV K1 to that with floating BRV K1 to obtain the lowest possible BRV K1; the same analysis was performed to find the highest LEV K1. The lower bound of the ratio BRV K1/LEV K1 was ~ 7.ConclusionsUnder appropriate conditions, this advanced nonlinear model can directly estimate entry rates of drugs into tissue by analysis of PET TACs. Using a conservative statistical cutoff, BRV enters the brain at least sevenfold faster than LEV.

PurposeThe aim of this study was to evaluate different non-invasive methods for generating (R)-1-((3-([11C]methyl)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([11C]UCB-J) parametric maps using white matter (centrum semi-ovale–SO) as reference tissue.ProceduresTen healthy volunteers (8 M/2F; age 27.6 ± 10.0 years) underwent a 90-min dynamic [11C]UCB-J positron emission tomography (PET) scan with full arterial blood sampling and metabolite analysis before and after administration of a novel chemical entity with high affinity for presynaptic synaptic vesicle glycoprotein 2A (SV2A). A simplified reference tissue model (SRTM2), multilinear reference tissue model (MRTM2), and reference Logan graphical analysis (rLGA) were used to generate binding potential maps using SO as reference tissue (BPSO). Shorter dynamic acquisitions down to 50 min were also considered. In addition, standard uptake value ratios (SUVR) relative to SO were evaluated for three post-injection intervals (SUVRSO,40-70min, SUVRSO,50-80min, and SUVRSO,60-90min respectively). Regional parametric BPSO + 1 and SUVRSO were compared with regional distribution volume ratios of a 1-tissue compartment model (1TCM DVRSO) using Spearman correlation and Bland-Altman analysis.ResultsFor all methods, highly significant correlations were found between regional, parametric BPSO + 1 (r = [0.63;0.96]) or SUVRSO (r = [0.90;0.91]) estimates and regional 1TCM DVRSO. For a 90-min dynamic scan, parametric SRTM2 and MRTM2 values presented similar small bias and variability (− 3.0 ± 2.9 % for baseline SRTM2) and outperformed rLGA (− 10.0 ± 5.3 % for baseline rLGA). Reducing the dynamic acquisition to 60 min had limited impact on the bias and variability of parametric SRTM2 BPSO estimates (− 1.0 ± 9.9 % for baseline SRTM2) while a higher variability (− 1.83 ± 10.8 %) for baseline MRTM2 was observed for shorter acquisition times. Both SUVRSO,60-90min and SUVRSO,50-80min showed similar small bias and variability (− 2.8 ± 4.6 % bias for baseline SUVRSO,60-90min).ConclusionSRTM2 is the preferred method for a voxelwise analysis of dynamic [11C]UCB-J PET using SO as reference tissue, while reducing the dynamic acquisition to 60 min has limited impact on [11C]UCB-J BPSO parametric maps. For a static PET protocol, both SUVRSO,60-90min and SUVRSO,50-80min images are an excellent proxy for [11C]UCB-J BPSO parametric maps.

Group 1 metabotropic glutamate subtype 5 receptors (mGluR5) contribute to the control of motor behavior by regulating the balance between excitation and inhibition of outputs in the basal ganglia. The density of these receptors is increased in patients with Parkinson’s disease and motor complications. We hypothesized that similar changes may occur in Huntington’s disease (HD) and aimed at testing this hypothesis in a preliminary experimental series in postmortem human brain material obtained from HD patients. Using autoradiography, we analyzed mGluR5 density in the putamen, caudate nucleus and cerebellum (control region) in postmortem tissue samples from three patients with HD and three controls with two mGluR5-specific radioligands ([ 3 H]ABP688 and [ 11 C]ABP688). The density of enkephalin (Enk)- or substance P (SP)-containing neurons was assessed using immunohistochemical and cell-counting methods. [ 3 H]ABP688 binding in HD was reduced in the caudate (−70.4 %, P  < 0.001), in the putamen (−33.3 %, P  = 0.053), and in the cerebellum (−8.79 %, P  = 0.930) vs controls. Results with [ 11 C]ABP688 were similar; there was good correlation between [ 11 C]ABP688 and [ 3 H]ABP688 binding ratios. Total cell density was similar in all three brain regions in HD patients and controls. Neuronal density was 69 % lower in the caudate ( P  = 0.002) and 64 % lower in the putamen ( P  < 0.001) of HD patients vs controls. Both direct and indirect pathways were affected, with ≥90 % decrease in the density of Enk- and SP-containing neurons in the caudate and putamen of HD patients vs controls ( P  < 0.001). In contrast to earlier observations in PD, in HD, compared to controls, the mGluR5 density was significantly lower in the caudate nucleus. The decrease in neuronal density suggests that neuronal loss was largely responsible for the observed decrease in mGluR5.

In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner.PURPOSEIn a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner.Two rhesus monkeys were examined using a high-resolution PET system with (S,S)-[(18)F]FMeNER-D(2) under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BP(ND) obtained with the simplified reference tissue model.METHODSTwo rhesus monkeys were examined using a high-resolution PET system with (S,S)-[(18)F]FMeNER-D(2) under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BP(ND) obtained with the simplified reference tissue model.NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml.RESULTSNET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml.The results indicate that clinical doses of atomoxetine would occupy NET almost completely.CONCLUSIONThe results indicate that clinical doses of atomoxetine would occupy NET almost completely.

Purpose: In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner. Methods: Two rhesus monkeys were examined using a high-resolution PET system with (S,S)-[ super(18)F]FMe NER-D sub(2) under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BP sub(ND) obtained with the simplified reference tissue model. Results: NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16ng/ml. Conclusion: The results indicate that clinical doses of atomoxetine would occupy NET almost completely.

Purpose In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner. Methods Two rhesus monkeys were examined using a high-resolution PET system with ( S , S )-[ 18 F]FMeNER-D 2 under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BP ND obtained with the simplified reference tissue model. Results NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml. Conclusion The results indicate that clinical doses of atomoxetine would occupy NET almost completely.