Santiago Bullich

Trans-Synaptic Axonal Degeneration in the Visual Pathway in Multiple Sclerosis

To evaluate the association between the damage to the anterior and posterior visual pathway as evidence of the presence of retrograde and anterograde trans‐synaptic degeneration in multiple sclerosis (MS).

Translational characterization of [11C]GSK931145, a PET ligand for the glycine transporter type 1

The current interest in developing Glycine transporter Type 1 (GlyT‐1) inhibitors, for diseases such as schizophrenia, has led to the demand for a GlyT‐1 PET molecular imaging tool to aid drug development and dose selection. We report on [11C]GSK931145 as a novel GlyT‐1 imaging probe in primate and man. Primate PET studies were performed to determine the level of specific binding following homologous competition with GSK931145 and the plasma‐occupancy relationship of the GlyT‐1 inhibitor GSK1018921. Human PET studies were performed to determine the test–retest reproducibility of [11C]GSK931145 and the plasma‐occupancy relationship of GSK1018921. [11C]GSK931145 entered primate and human brain and yielded a heterogeneous pattern of uptake which was similar in both species with highest uptake in midbrain, thalamus, and cerebellum. Homologous competition in primates indicated no viable reference region and gave binding potential estimates between 1.5 and 3 for midbrain, thalamus and cerebellum, While the distribution and binding potential values were similar across species, both the plasma free fraction (fP: 0.8 vs. 8%) and delivery (K1: 0.025 vs. 0.126 ml cm−3 min−1) were significantly lower in humans. Test–retest reproducibility in humans calculated using a two tissue compartmental model was poor (VAR(VT): 29–38%), but was improved using a pseudo reference tissue model (VAR(BPND): 16–23%). GSK1018921 EC50 estimates were 22.5 and 45.7 ng/ml in primates and humans, respectively. Synapse, 2011.

Amyloid PET imaging: applications beyond Alzheimer's disease.

As a biomarker of beta-amyloid, positron emission tomography (PET) amyloid imaging offers a unique opportunity to detect the presence of this protein in the human body during life. Besides Alzheimer’s disease (AD), deposits of beta-amyloid in the brain are also present in other neurodegenerative diseases associated to dementia, such as Parkinson’s disease and dementia with Lewy bodies, as well as in other processes affecting brain function, such as cerebral amyloid angiopathy, brain trauma, Down’s syndrome and meningiomas, as shown by post-mortem pathology studies. Furthermore, in systemic amyloidosis other organs besides the brain are affected, and amyloid PET imaging may be suitable for the identification of these extra-cerebral amyloid depositions. Finally, the potential use of amyloid PET tracer accumulation in cerebral white matter (WM) as a marker of myelin is being investigated, leading to some promising results in patients with WM lesions and multiple sclerosis. In this article, a review of the ongoing research pointing to a broader application of amyloid PET imaging in clinical practice beyond AD is provided.

Within-subject comparison of striatal D2 receptor occupancy measurements using [123I]IBZM SPECT and [11C]Raclopride PET.

Antipsychotic-induced D2 receptor occupancy values tend to be lower when measured with [(123)I]IBZM SPECT than with [(11)C]Raclopride PET. To clarify this issue, D2 receptor occupancy was measured in the same subjects using both techniques. Twenty patients with schizophrenia on monotherapy with risperidone (n=7; 3-9 mg/d), olanzapine (n=5; 5-20 mg/d) or clozapine (n=8; 150-450 mg/d) at stable doses, and ten healthy volunteers (HV) underwent both a [(123)I]IBZM SPECT and a [(11)C]Raclopride PET examinations in random order on different days within a week. Patients with schizophrenia were scanned at a fixed interval after last dose administration. Quantification of receptor availability was performed using the most conventional methods from the literature: the tissue ratio derived specific uptake ratios (SUR) were used for SPECT, and simplified reference tissue model (SRTM) derived binding potentials (BP(ND)) for PET. Analysis was performed using both occipital cortex and cerebellum as reference regions for both modalities. Striatal D2 receptor occupancy was measured as the percentage reduction of [(123)I]IBZM SUR or [(11)C]Raclopride BP(ND) compared to the population average measured in HV using the same modality. Occupancy values measured by SPECT were lower than those measured with PET, by 12.4% and 13.8% when occipital cortex and cerebellum were used as reference regions. This difference should be taken in consideration when interpreting reported antipsychotic striatal D2 receptor occupancy values from the literature.

Quantification of dopaminergic neurotransmission SPECT studies with 123I-labelled radioligands. A comparison between different imaging systems and data acquisition protocols using Monte Carlo simulation

Purpose123I-labelled radioligands are commonly used for single-photon emission computed tomography (SPECT) imaging of the dopaminergic system to study the dopamine transporter binding. The aim of this work was to compare the quantitative capabilities of two different SPECT systems through Monte Carlo (MC) simulation.MethodsThe SimSET MC code was employed to generate simulated projections of a numerical phantom for two gamma cameras equipped with a parallel and a fan-beam collimator, respectively. A fully 3D iterative reconstruction algorithm was used to compensate for attenuation, the spatially variant point spread function (PSF) and scatter. A post-reconstruction partial volume effect (PVE) compensation was also developed.ResultsFor both systems, the correction for all degradations and PVE compensation resulted in recovery factors of the theoretical specific uptake ratio (SUR) close to 100%. For a SUR value of 4, the recovered SUR for the parallel imaging system was 33% for a reconstruction without corrections (OSEM), 45% for a reconstruction with attenuation correction (OSEM-A), 56% for a 3D reconstruction with attenuation and PSF corrections (OSEM-AP), 68% for OSEM-AP with scatter correction (OSEM-APS) and 97% for OSEM-APS plus PVE compensation (OSEM-APSV). For the fan-beam imaging system, the recovered SUR was 41% without corrections, 55% for OSEM-A, 65% for OSEM-AP, 75% for OSEM-APS and 102% for OSEM-APSV.ConclusionOur findings indicate that the correction for degradations increases the quantification accuracy, with PVE compensation playing a major role in the SUR quantification. The proposed methodology allows us to reach similar SUR values for different SPECT systems, thereby allowing a reliable standardisation in multicentric studies.

Bilastine vs. hydroxyzine: occupation of brain histamine H1‐receptors evaluated by positron emission tomography in healthy volunteers

Aim A close correlation exists between positron emission tomography (PET)-determined histamine H1-receptor occupancy (H1RO) and the incidence of sedation. Antihistamines with H1RO <20% are classified as non-sedating. The objective was to compare the H1RO of bilastine, a second generation antihistamine, with that of hydroxyzine. Methods This randomized, double-blind, crossover study used PET imaging with [11C]-doxepin to evaluate H1RO in 12 healthy males (mean age 26.2 years), after single oral administration of bilastine (20 mg), hydroxyzine (25 mg) or placebo. Binding potentials and H1ROs were calculated in five cerebral cortex regions of interest: frontal, occipital, parietal, temporal, insula. Plasma bilastine concentrations, subjective sedation (visual analogue scale), objective psychomotor performance (digital symbol substitution test), physiological variables and safety (adverse events, AEs), were also evaluated. Results The mean binding potential of all five regions of interest (total binding potential) was significantly greater with bilastine than hydroxyzine (mean value 0.26 vs. 0.13, P < 0.01; mean difference and 95% CI −0.130 [−0.155, 0.105]). There was no significant difference between bilastine and placebo. Overall H1RO by bilastine was significantly lower than that by hydroxyzine (mean value −3.92% vs. 53.95%, P < 0.01; mean difference and 95% CI 57.870% [42.664%, 73.075%]). There was no significant linear relationship between individual bilastine plasma concentrations and total binding potential values. No significant between-treatment differences were observed for sedation and psychomotor performance. Twenty-six non-serious AEs were reported. Sleepiness or sedation was not reported with bilastine but appeared in some subjects with hydroxyzine. Conclusions A single oral dose of bilastine 20 mg had minimal H1RO, was not associated with subjective sedation or objective impairment of psychomotor performance and was devoid of treatment-related sedative AEs, thus satisfying relevant subjective, objective and PET criteria as a non-sedating antihistamine.

Imaging Cortical Dopamine D1 Receptors Using [11C]NNC112 and Ketanserin Blockade of the 5-HT2A Receptors

[11C]NNC112 (8-chloro-7-hydroxy-3-methyl-5-(7-benzofuranyl)-2,3,4,5-tetrahydro-IH-3-benzazepine), a selective positron-emission tomography (PET) ligand for the D1 receptor (R) over the 5-HT2A R in vitro, has shown lower selectivity in vivo, hampering measurement of D1 R in the cortex. [11C]NNC112 PET and intravenous (i.v) ketanserin challenge were used to (1) confirm the previous findings of [11C]NNC112 in vivo D1 R selectivity, and (2) develop a feasible methodology for imaging cortical D1 R without contamination by 5-HT2A R. Seven healthy volunteers underwent [11C]NNC112 PET scans at baseline and after a 5-HT2A R-blocking dose of ketanserin (0.15 mg/kg, i.v.). Percent BPND change between the post-ketanserin and baseline scans was calculated. Irrespective of the quantification method used, ketanserin pretreatment led to significant decrease of BPND in the cortical (∼30%) and limbic regions (∼20%) but not in the striatum, which contains a much lower amount of 5-HT2A R. Therefore, ketanserin allows D1 R signal to be detected by [11C]NNC112 PET without significant 5-HT2A R contamination. These data confirm the presence of a significant 5-HT2A R contribution to cortical [11C]NNC112 signal, and call for caution in the interpretation of published [11C]NNC112 PET findings on cortical D1 R in humans. In the absence of more selective ligands, [11C]NNC112 PET with ketanserin can be used for cortical D1 R imaging in vivo.

Impact of Training Method on the Robustness of the Visual Assessment of 18F-Florbetaben PET Scans: Results from a Phase-3 Study.

Training for accurate image interpretation is essential for the clinical use of β-amyloid PET imaging, but the role of interpreter training and the accuracy of the algorithm for routine visual assessment of florbetaben PET scans are unclear. The aim of this study was to test the robustness of the visual assessment method for florbetaben scans, comparing efficacy readouts across different interpreters and training methods and against a histopathology standard of truth (SoT). Methods: Analysis was based on data from an international open-label, nonrandomized, multicenter phase-3 study in patients with or without dementia (ClinicalTrials.gov: NCT01020838). Florbetaben scans were assessed visually and quantitatively, and results were compared with amyloid plaque scores. For visual assessment, either in-person training (n = 3 expert interpreters) or an electronic training method (n = 5 naïve interpreters) was used. Brain samples from participants who died during the study were used to determine the histopathologic SoT using Bielschowsky silver staining (BSS) and immunohistochemistry for β-amyloid plaques. Results: Data were available from 82 patients who died and underwent postmortem histopathology. When visual assessment results were compared with BSS + immunohistochemistry as SoT, median sensitivity was 98.2% for the in-person–trained interpreters and 96.4% for the e-trained interpreters, and median specificity was 92.3% and 88.5%, respectively. Median accuracy was 95.1% and 91.5%, respectively. On the basis of BSS only as the SoT, median sensitivity was 98.1% and 96.2%, respectively; median specificity was 80.0% and 76.7%, respectively; and median accuracy was 91.5% and 86.6%, respectively. Interinterpreter agreement (Fleiss κ) was excellent (0.89) for in-person–trained interpreters and very good (0.71) for e-trained interpreters. Median intrainterpreter agreement was 0.9 for both in-person–trained and e-trained interpreters. Visual and quantitative assessments were concordant in 88.9% of scans for in-person–trained interpreters and in 87.7% of scans for e-trained interpreters. Conclusion: Visual assessment of florbetaben images was robust in challenging scans from elderly end-of-life individuals. Sensitivity, specificity, and interinterpreter agreement were high, independent of expertise and training method. Visual assessment was accurate and reliable for detection of plaques using BSS and immunohistochemistry and well correlated with quantitative assessments.

Cerebellar Amyloid-β Plaques: How Frequent Are They, and Do They Influence 18F-Florbetaben SUV Ratios?

SUV ratios (SUVRs) are used for relative quantification of 18F-florbetaben scans. The cerebellar cortex can be used as a reference region for quantification. However, cerebellar amyloid-β (Aβ) plaques may be present in Alzheimer disease (AD). The aim of this study was to assess the influence of Aβ pathology, including neuritic plaques, diffuse plaques, and vascular deposits, in 18F-florbetaben SUVR when cerebellum is used as the reference. Methods: Using immunohistochemistry to demonstrate Aβ plaques and vascular deposits, and using the Bielschowsky method to demonstrate neuritic plaques, we performed a neuropathologic assessment of the frontal, occipital, anterior cingulate, and posterior cingulate cerebral cortices and the cerebellar cortex of 87 end-of-life patients (64 with AD, 14 with other types of dementia, and 9 nondemented aged volunteers; mean age ± SD, 80.4 ± 10.2 y) who had undergone 18F-florbetaben PET before death. The lesions were rated as absent (none or sparse) or present (moderate or frequent). Mean cortical SUVRs were compared among cases with different cerebellar Aβ loads. Results: None of the 83 evaluable cerebellar samples showed frequent diffuse Aβ or neuritic plaques; 8 samples showed frequent vascular Aβ deposits. Diffuse Aβ plaques were rated as absent in 78 samples (94%) and present in 5 samples (6%). Vascular Aβ was rated as absent in 62 samples (74.7%) and present in 21 samples (25.3%). No significant differences in cerebellar SUVs were found among cases with different amounts or types of Aβ deposits in the cerebral cortex. Both diffuse and neuritic plaques were found in the cerebral cortex of 26–44 cases. No significant SUVR differences were found between these brains with different cerebellar Aβ loads. Conclusion: The effect of cerebellar plaques on cortical 18F-florbetaben SUVRs appears to be negligible even in advanced stages of AD with a higher cerebellar Aβ load.

Contribution of SPECT Measurements of D2 and 5-HT2A Occupancy to the Clinical Development of the Antipsychotic SB-773812

The aim of this study was to assess human striatal dopamine receptor 2 (D2) and cortical 5-hydroxytryptamine receptor 2A (5-HT2A) occupancy of SB-773812 to demonstrate brain penetration and binding to the target receptors and assess the pharmacokinetics–receptor occupancy relationship over time to aid dose selection and dosage regimen, in preparation for the phase II trials. Methods: D2 and 5-HT2A occupancy were measured over time (both at the time of maximum [Tmax; 6 ± 2 h] and at the time of minimum [Ttrough; 24 ± 4 h] plasma concentration after dosing) by means of 123I-iodobenzamide and 123I-4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide (123I-R91150) SPECT in 3 studies. Study A consisted of SB-773812 single doses in healthy volunteers—D2 occupancy measured at 48 (n = 9) and 56 mg (n = 9) and 5-HT2A occupancy at 56 mg (n = 9); study B consisted of D2 and 5-HT2A occupancy measured in 12 stabilized-schizophrenia patients on stable doses (16–18 d of 56 mg/d) after washout of previous medication; and study C included D2 occupancy measured in a double-blind study of patients with acutely exacerbated schizophrenia (n = 10) on stable doses (18–21 d) of SB-773812 (100 mg/d; n = 7) or risperidone (6 mg/d; n = 3). Results: Study A showed less than 30% D2 occupancy at Tmax, maintained at Ttrough. 5-HT2A occupancy was 74%–97% and also maintained over time. Study B revealed that 8 of the 12 schizophrenia patients showed more than 40% D2 occupancy. 5-HT2A occupancy ranged from 91% to 100%. In study C, SB-773812–induced D2 occupancy was 60.3% ± 13.3% at Tmax and 55.1% ± 4.9% at Ttrough. The pharmacokinetics–receptor occupancy relationship was assessed in each study and strengthened, combining all data to yield a concentration associated with 50% occupancy (EC50) of 92.7 ± 13.5 ng/mL for D2 and 2.11 ± 0.50 ng/mL for 5-HT2A. Conclusion: In all subjects, SB-773812 showed penetration into the brain, reaching its target receptors. In patients with schizophrenia, D2 occupancy levels induced by a single dose were maintained over time, indicating that once-daily dosing regimens are appropriate. Pharmacokinetics–receptor occupancy analysis provided guidance for the selection of a clinically effective dose, supporting progression in phase II.