Zsolt Cselényi

Head-to-Head Comparison of 11C-PiB and 18F-AZD4694 (NAV4694) for β-Amyloid Imaging in Aging and Dementia

11C-Pittsburgh compound-B (11C-PiB) is the benchmark radiotracer for imaging of β-amyloid (Aβ) plaque in Alzheimer disease (AD). 18F-labeled Aβ tracers subsequently developed for clinical use show higher nonspecific white matter binding and, in some cases, lower cortical binding in AD that could lead to less accurate interpretation of scans. We compared the cortical and white matter binding of a new 18F-labeled Aβ tracer, 18F-AZD4694 (recently renamed NAV4694), with 11C-PiB in the same subjects. Methods: Forty-five participants underwent PET imaging with 11C-PiB and 18F-AZD4694 (25 healthy elderly controls [HCs], 10 subjects with mild cognitive impairment, 7 subjects with probable AD, and 3 subjects with probable frontotemporal dementia). Images were coregistered so that region-of-interest placement was identical on both scans, and standardized uptake value ratios (SUVRs) using the cerebellar cortex as a reference region were calculated between 40 and 70 min after injection for both tracers. Results: 18F-AZD4694 showed reversible binding kinetics similar to 11C-PiB, reaching an apparent steady state at 50 min after injection. Both radiotracers showed a similar dynamic range of neocortical SUVR (1.1–3.3 and 1.0–3.2 SUVR for 11C-PiB and 18F-AZD4694, respectively) and identical low nonspecific white matter binding, with frontal cortex–to–white matter ratios of 0.7 ± 0.2 and 1.3 ± 0.2 for both radiotracers in HCs and AD subjects, respectively. There was an excellent linear correlation between 11C-PiB and 18F-AZD4694 neocortical SUVR (slope of 0.95, r = 0.99, P < 0.0001). Conclusion: 18F-AZD4694 displays imaging characteristics nearly identical to those of 11C-PiB. The low white matter and high cortical binding in AD indicate that this tracer is well suited to both clinical and research use.

Detection of amyloid in Alzheimer’s disease with positron emission tomography using [11C]AZD2184

PurposeCurrent positron emission tomography (PET) radioligands for detection of Aβ amyloid in Alzheimer’s disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [11C]AZD2184 and report here the first clinical evaluation.MethodsEight AD patients and four younger control subjects underwent 93-min PET measurements with [11C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters.ResultsBrain uptake of [11C]AZD2184 peaked within 1 min at 3–4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57.Conclusion[11C]AZD2184 is a promising radioligand for detailed mapping of Aβ amyloid depositions in Alzheimer’s disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium.

Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain - a PET study in control subjects

BackgroundPositron-emission tomography and the radioligand [11C](R)-PK11195 have been used for the imaging of the translocator protein (TSPO) and applied to map microglia cells in the brain in neuropsychiatric disorders. [11C](R)-PK11195 binding has been quantified using reference region approaches, with the reference defined anatomically or using unsupervised or supervised clustering algorithms. Kinetic compartment modelling so far has not been presented. In the present test-retest study, we examine the characteristics of [11C](R)-PK11195 binding in detail, using the classical compartment analysis with a metabolite-corrected arterial input function.Methods[11C](R)-PK11195 binding was examined in six control subjects at two separate occasions, 6 weeks apart. Results of one-tissue and two-tissue compartment models (1TCM, 2TCM) were compared using the Akaike criteria and F-statistics. The reproducibility of binding potential (BPND) estimates was evaluated by difference in measurements (error in percent) and intraclass correlation coefficients (ICCs).Results[11C](R)-PK11195 binding could be described by 2TCM which was the preferred model. Measurement error (in percent) indicated good reproducibility in large brain regions (mean error: whole brain 4%, grey matter 5%), but not in smaller subcortical regions (putamen 25%, caudate 55%). The ICC values were moderate to low, highest for the white matter (0.73), whole brain and thalamus (0.57), and cortical grey matter (0.47). Sizeable [11C](R)-PK11195 BPND could be identified throughout the human brain (range 1.11 to 2.21).ConclusionsHigh intra-subject variability of [11C](R)-PK11195 binding limits longitudinal monitoring of TSPO changes. The interpretation of [11C](R)-PK11195 binding by 2TCM suggests that the presence of specific binding to TSPO cannot be excluded at physiological conditions.

Quantification of serotonin transporter availability with [11C]MADAM--a comparison between the ECAT HRRT and HR systems.

UNLABELLEDnThe High Resolution Research Tomograph (HRRT) is the PET system providing the highest resolution for imaging of the human brain. In this study, the improved quantitative performance of the HRRT was evaluated in comparison with a previously developed lower resolution PET system, the ECAT HR. The radioligand [(11)C]MADAM was chosen for the purpose since it provides a signal for serotonin transporter (5-HTT) binding in cortical and sub-cortical brain regions of different sizes and expressing different 5-HTT densities. A secondary objective was to assess the effect of partial volume effect (PVE) correction on the cross-comparability between the two systems.nnnMETHODnSix male control subjects (ages 20-35 yr) were examined twice using the HRRT and the HR system, respectively. Regions of interest (ROIs) included cortical regions (frontal cortex, temporal cortex, insula, anterior cingulate cortex, and hippocampus), sub-cortical regions (caudate, putamen, thalamus, dorsal brainstem and ventral midbrain) and cerebellum. The ROIs were manually delineated on T1-weighted MRI-images and subsequently applied to both HRRT and HR images. Regional binding potential (BP(ND)) values were calculated with the simplified reference tissue model (SRTM) using cerebellum as the reference region. The percent difference in BP(ND) between the systems was calculated for each ROI. In addition, both HRRT and HR data were corrected for PVE using established MRI-based methods described by Meltzer and Müller-Gärtner. The effect of PVE correction (PVEc) on the agreement between the systems was assessed via percent difference calculation and linear regression analysis.nnnRESULTSnQuantification with SRTM showed that regional BP(ND) values for [(11)C]MADAM were on average 23% higher for the HRRT than those obtained by the HR system. More specifically, BP(ND) measured with HRRT was 31.1±48.1% higher in neocortical/limbic regions and 14.6±20.9% higher in sub-cortical regions. The effect of PVEc varied between regions. After correction according to Müller-Gärtner, the agreement between systems was best in the neocortical/limbic regions (3.7±22.5%). With the exception of the caudate, in which the agreement was improved by approximately 17% using the Meltzer method, the effect of PVEc in sub-cortical regions was less pronounced. Linear regression analysis showed improved correlation between the two systems after PVEc, particularly in the neocortical/limbic regions.nnnCONCLUSIONnAs expected, BP(ND) values measured with the HRRT were higher than those measured with the HR due to higher resolution and recovery. The difference in BP(ND) between the two systems was approximately 30% in the neocortical/limbic regions. PVEc improved the agreement between the systems in particular for the neocortical/limbic regions. In these regions, the best agreement was found after applying Müller-Gärtners PVEc. The demonstrated agreement provides an opportunity for combining data between the two systems in clinical studies aimed at evaluating receptor/transporter availability in cortical brain regions.

A positron emission tomography study in healthy volunteers to estimate mGluR5 receptor occupancy of AZD2066 — Estimating occupancy in the absence of a reference region

AZD2066 is a new chemical entity pharmacologically characterized as a selective, negative allosteric modulator of the metabotropic glutamate receptor subtype 5 (mGluR5). Antagonism of mGluR5 has been implicated in relation to various diseases such as anxiety, depression, and pain disorders. To support translation from preclinical results and previous experiences with this target in man, a positron emission tomography study was performed to estimate the relationship between AZD2066 plasma concentrations and receptor occupancy in the human brain, using the mGluR5 radioligand [(11)C]-ABP688. The study involved PET scans on 4 occasions in 6 healthy volunteers. The radioligand was given as a tracer dose alone and following oral treatment with different doses of AZD2066. The analysis was based on the total volume of distribution derived from each PET-assessment. A non-linear mixed effects model was developed where ten delineated brain regions of interest from all PET scans were included in one simultaneous fit. For comparison the analysis was also performed according to a method described previously by Lassen et al. (1995). The results of the analysis showed that the total volume of distribution decreased with increasing drug concentrations in all regions with an estimated Kipl of 1170 nM. Variability between individuals and occasions in non-displaceable volume of distribution could explain most of the variability in the total volume of distribution. The Lassen approach provided a similar estimate for Kipl, but the variability was exaggerated and difficult to interpret.

Radiosynthesis of the candidate β‐amyloid radioligand [11C]AZD2184: Positron emission tomography examination and metabolite analysis in cynomolgus monkeys

β‐Amyloid accumulation is associated with the pathogenesis of Alzheimers disease (AD). AZD2184, a new radioligand for high‐contrast positron emission tomography (PET) imaging of Aβ‐deposits, has recently been developed and characterized in vitro and in rodents ex vivo. The objective of this study was to label AZD2184 with carbon‐11, to perform in vivo characterization of [11C]AZD2184 ([11C]5) in the cynomolgus monkey brain as well as whole‐body dosimetry, and to examine the metabolism of the labeled radioligand. [11C]5 was prepared by a two‐step radiosynthesis starting with the reaction of 5‐(6‐(tert‐butyldimethylsilyloxy)benzo[d]thiazol‐2‐yl)pyridin‐2‐amine with [11C]methyl iodide followed by deprotection using water. Four brain PET measurements in two cynomolgus monkeys and one whole‐body PET measurement were performed with [11C]5. There was a high and rapid brain uptake (2.2–3.4% of injected dose at 2 min). The distribution of brain radioactivity was fairly uniform, with early to late‐brain concentration ratios (peak vs. 60 min) higher for [11C]5 than ratios previously reported for [11C]PIB (8.2 and 4.6, respectively). Based on the whole‐body data, it was estimated that an effective dose in an adult male would be 6.2 μSv/MBq and thus would be safe from a radiation point of view for multiple scans within the same year. [11C]5 shows binding characteristics, suggesting low levels of white‐matter retention, and may thus provide improved contrast when compared with currently used PET radioligands for visualization of Aβ‐deposits. On the basis of the labeling chemistry and the results of the biological evaluation, we conclude that [11C]5 should be useful for routine clinical studies. Synapse 64:733–741, 2010.

Non-linear mixed effects modelling of positron emission tomography data for simultaneous estimation of radioligand kinetics and occupancy in healthy volunteers

The aim of this work was to develop a model simultaneously estimating (11)C-AZD9272 radioligand kinetics and the relationship between plasma concentration of AZD9272 and receptor occupancy in the human brain. AZD9272 is a new chemical entity pharmacologically characterised as a noncompetitive antagonist at the metabotropic glutamate receptor subtype 5 (mGluR5). Positron emission tomography (PET) was used to measure the time course of ((11)C-AZD9272) in the brain. The study included PET measurements in six healthy volunteers where the radioligand was given as a tracer dose alone as well as post oral treatment with different doses of unlabelled AZD9272. Estimation of radioligand kinetics, including saturation of receptor binding was performed by use of non-linear mixed effects modelling. Data from the regions with the highest (ventral striatum) and lowest (cerebellum) radioligand concentrations were included in the analysis. It was assumed that the extent of non-displaceable brain uptake was the same in both regions while the rate of CNS uptake and the receptor density differed. The results of the analysis showed that AZD9272 binding at the receptor is saturable with an estimated plasma concentration corresponding to 50% occupancy of approximately 200 nM. The density of the receptor binding sites was estimated to 800 nM and 200 nM in ventral striatum and cerebellum respectively. By simultaneously analysing data from several PET measurements and different brain regions in a non-linear mixed effects framework it was possible to estimate parameters of interest that would otherwise be difficult to quantify.

Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369

RationaleThe serotonin 5-HT1B receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT1B receptor occupancy with drug candidates targeting this receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT1B receptor antagonist with potential antidepressant properties.ObjectivesTo determine the relationship between plasma concentration of AZD3783 and occupancy at primate brain 5-HT1B receptors using PET and the radioligand [11C]AZ10419369.MethodsPET studies with [11C]AZ10419369 were performed in three non-human primates at baseline and after intravenous injection of AZD3783. Subsequently, PET measurements were undertaken in six human subjects at baseline and after administration of different single oral doses of AZD3783 (1–40xa0mg).ResultsAfter administration in non-human primates and human subjects, AZD3783 reduced regional [11C]AZ10419369 binding in a dose-dependent and saturable manner. The AZD3783 plasma concentration required for 50% receptor occupancy (Ki,plasma) for monkeys was 25 and 27xa0nmol/L in occipital cortex and striatum, respectively. Corresponding estimates for human occipital cortex and ventral striatum were 24 and 18xa0nmol/L, respectively.ConclusionsThe potential antidepressant AZD3783 binds in a saturable manner to brain 5-HT1B receptors with a similar in vivo affinity for human and monkey receptors. [11C]AZ10419369 can be successfully used to determine occupancy at brain 5-HT1B receptors in vivo and constitutes a useful tool for dose selection in clinical studies with 5-HT1B receptor compounds.

Evaluation of Two Automated Methods for PET Region of Interest Analysis

Manual definition of regions of interest (ROIs) has been considered the reference standard method in PET data evaluation. The method is labor-intensive, prone to rater bias and may show low reproducibility. Automated template-based methods for ROI definition may overcome these limitations. The aim of this study was to validate the two automated methods FreeSurfer and the AAL template for definition of ROIs for the PET data analysis. PET data obtained using the radioligands [11C]AZD2184 (amyloid-β radioligand) and [11C]AZ10419369 (5-HT1B receptor radioligand) were evaluated. PET measurements acquired on one high and one lower resolution PET system were included. Outcome measures obtained using automated methods were compared to those obtained using manual ROIs, using linear regression analysis, intraclass correlation coefficients, and repeated measures ANOVA. ROIs provided by the automatic methods were larger than the manually delineated regions, which in some cases introduced biased estimates of the outcome measures. However, with the exception of the caudate, both AAL and FreeSurfer generally provided outcome measures that were in good agreement to those obtained from manually delineated ROIs, as long as the manually defined cerebellum was used as a reference region. Both AAL and FreeSurfer can be used for quantification of PET data, with similar accuracy in the estimates of outcome measures. Thus, the choice of method could be based upon necessity of fast analysis as provided by AAL, or more detailed ROIs and measures of cortical thickness as provided by FreeSurfer.

Norepinephrine transporter occupancy in the human brain after oral administration of quetiapine XR

Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET). This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiapine XR) at doses relevant in the treatment of depression. PET measurements using the specific NET radioligand (S,S)-[(18)F]FMeNER-D2 were performed before and after quetiapine XR treatment at 150 and 300 mg/d for 6-8 d in nine healthy males (aged 21-33 yr). Regions of interest were defined for the thalamus, using the caudate as reference region. NET occupancy was calculated using a target:reference region ratio method. Plasma concentrations of quetiapine and norquetiapine were monitored during PET measurements. Following quetiapine XR treatment, the mean NET occupancy in the thalamus was 19 and 35%, respectively, at quetiapine XR doses of 150 and 300 mg/d. The estimated plasma concentration of norquetiapine corresponding to 50% NET occupancy was 161 ng/ml. This is the first demonstration of NET occupancy by an antipsychotic in the human brain. NET inhibition is accepted as a mechanism of antidepressant activity. NET occupancy may therefore contribute to the broad spectrum of efficacy of quetiapine.