Christer Halldin

Radioligand Disposition and Metabolism — Key Information in Early Drug Development

The majority of drugs and other organic compounds that are considered foreign to the body undergoes metabolic changes in vivo. Most drugs are metabolized by a system of enzymes of low substrate specificity requirement which is present mainly in the liver but drug metabolism may also take place in the kidneys and lungs. The various products obtained by the metabolism are identified in terms of concentrations and kinetics. Drug metabolism has been described as a detoxication of potentially harmful substances from the environment. This is not strictly true since the resulting products and metabolites can also be toxic. Drugs can undergo many different types of biochemical reactions, which can be divided into four main types, namely, oxidations, reductions, hydrolysis and synthesis. Radiopharmaceuticals are like any other drugs or compounds liable to chemical transformation after their administration in vivo to humans. For radiopharmaceuticals we are only concerned with the parent compound and its radioactive metabolites [1].

PET-determination of benzodiazepine receptor binding in studies on alcoholism

Positron Emission Tomography (PET) and the radioligand [11C]flumazenil were used to examine benzodiazepine (BZ) receptor binding in the human brain. In a first study of healthy males acute ingestion of alcohol did not alter total radioactivity uptake or specific [11C]flumazenil binding in the neocortex or cerebellum. In a second study [11C]flumazenil binding was determined in 5 healthy male controls and 5 chronic alcohol dependent men using a saturation procedure with two PET experiments. Mean values for BZ-receptor density and affinity were similar in the two groups but the Bmax variance for the alcohol dependents was significantly larger (p < 0.05) for all regions. The present studies do not support the view that alcohol affects central BZ receptor binding in man.

Low serotonin1B receptor binding potential in the anterior cingulate cortex in drug-free patients with recurrent major depressive disorder.

The pathophysiology of major depressive disorder (MDD) is not fully understood and the diagnosis is largely based on history and clinical examination. So far, several lines of preclinical data and a single imaging study implicate a role for the serotonin1B (5-HT1B) receptor subtype. We sought to study 5-HT1B receptor binding in brain regions of reported relevance in patients with MDD. Subjects were examined at the Karolinska Institutet PET centre using positron emission tomography (PET) and the 5-HT1B receptor selective radioligand [(11)C]AZ10419369. Ten drug-free patients with recurrent MDD and ten control subjects matched for age and sex were examined. The main outcome measure was [(11)C]AZ10419369 binding in brain regions of reported relevance in the pathophysiology of MDD. The [(11)C]AZ10419369 binding potential was significantly lower in the MDD group compared with the healthy control group in the anterior cingulate cortex (20% between-group difference), the subgenual prefrontal cortex (17% between-group difference), and in the hippocampus (32% between-group difference). The low anterior cingulate [(11)C]AZ10419369 binding potential in patients with recurrent MDD positions 5-HT1B receptor binding in this region as a putative biomarker for MDD and corroborate a role of the anterior cingulate cortex and associated areas in the pathophysiology of recurrent MDD.

Nigrostriatal dopamine transporter availability in early Parkinson's disease: Nigro-Striatal Degeneration in Early Phases of PD

Background: The imaging of biomarkers for characterization of dopaminergic impairment in Parkinsons disease (PD) is useful for diagnosis, patient stratification, and assessment of treatment outcomes. [18F]FE‐PE2I is an improved imaging tool allowing for detailed mapping of the dopamine transporter protein in the nigro‐striatal system at the level of cell bodies (substantia nigra), axons, and presynaptic terminals (striatum).

Reliability of volumetric and surface-based normalisation and smoothing techniques for PET analysis of the cortex: A test-retest analysis using [ 11 C]SCH-23390

ABSTRACT Parametric voxelwise analysis is a commonly used tool in neuroimaging, as it allows for identification of regions of effects in the absence of a strong a‐priori regional hypothesis by comparing each voxel of the brain independently. Due to the inherent imprecision of single voxel measurements, spatial smoothing is performed to increase the signal‐to‐noise ratio of single‐voxel estimates. In addition, smoothing compensates for imprecisions in anatomical registration, and allows for the use of cluster‐based statistical thresholding. Smoothing has traditionally been applied in three dimensions, without taking the tissue types of surrounding voxels into account. This procedure may be suitable for subcortical structures, but is problematic for cortical regions for which grey matter often constitutes only a small proportion of the smoothed signal. New methods have been developed for cortical analysis in which voxels are sampled to a surface, and smoothing is restricted to neighbouring regions along the cortical grey matter in two dimensions. This procedure has recently been shown to decrease intersubject variability and bias of PET data. The aim of this study was to compare the variability, bias and test‐retest reliability of volumetric and surface‐based methods as they are applied in practice. Fifteen healthy young males were each measured twice using the dopamine D1 receptor radioligand [11C]SCH‐23390, and analyses were performed at the level of individual voxels and vertices within the cortex. We found that surface‐based methods yielded higher BPND values, lower coefficient of variation, less bias, better reliability and more precise estimates of parametric binding. All in all, these results suggest that surface‐based methods exhibit superior performance to volumetric approaches for voxelwise analysis of PET data, and we advocate for their use when a ROI‐based analysis is not appropriate. HIGHLIGHTSVolumetric and surface methods were compared for parametric cortical PET analysis.15 healthy controls were each measured twice using [11C]SCH‐23390.Surface methods yielded lower dispersion, less bias, and improved reliability.Surface methods are recommended for cortical analysis when ROIs are not appropriate.

Dual tracer tau PET imaging reveals different molecular targets for 11C-THK5351 and 11C-PBB3 in the Alzheimer brain

PurposeSeveral tau PET tracers have been developed, but it remains unclear whether they bind to the same molecular target on the heterogeneous tau pathology. In this study we evaluated the binding of two chemically different tau-specific PET tracers (11C-THK5351 and 11C-PBB3) in a head-to-head, in vivo, multimodal design.MethodsNine patients with a diagnosis of mild cognitive impairment or probable Alzheimer’s disease and cerebrospinal fluid biomarker evidence supportive of the presence of Alzheimer’s disease brain pathology were recruited after thorough clinical assessment. All patients underwent imaging with the tau-specific PET tracers 11C-THK5351 and 11C-PBB3 on the same day, as well as imaging with the amyloid-beta-specific tracer 11C-AZD2184, a T1-MRI sequence, and neuropsychological assessment.ResultsThe load and regional distribution of binding differed between 11C-THK5351 and 11C-PBB3 with no statistically significant regional correlations observed between the tracers. The binding pattern of 11C-PBB3, but not that of 11C-THK5351, in the temporal lobe resembled that of 11C-AZD2184, with strong correlations detected between 11C-PBB3 and 11C-AZD2184 in the temporal and occipital lobes. Global cognition correlated more closely with 11C-THK5351 than with 11C-PBB3 binding. Similarly, cerebrospinal fluid tau measures and entorhinal cortex thickness were more closely correlated with 11C-THK5351 than with 11C-PBB3 binding.ConclusionThis research suggests different molecular targets for these tracers; while 11C-PBB3 appeared to preferentially bind to tau deposits with a close spatial relationship to amyloid-beta, the binding pattern of 11C-THK5351 fitted the expected distribution of tau pathology in Alzheimer’s disease better and was more closely related to downstream disease markers.

Test-retest reproducibility of [11C]-l-deprenyl-D2 binding to MAO-B in the human brain

Background[11C]-l-deprenyl-D2 is a positron emission tomography (PET) radioligand for measurement of the monoamine oxidase B (MAO-B) activity in vivo brain. The estimation of the test-retest reproducibility is important for accurate interpretation of PET studies.ResultsWe performed two [11C]-l-deprenyl-D2 scans for six healthy subjects and evaluated the test-retest variability of this radioligand. MAO-B binding was quantified by two tissue compartment model (2TCM) with three rate constants (K1, k2, k3) using metabolite-corrected plasma radioactivity. The λk3 defined as (K1/k2)u2009×u2009k3 was also calculated. The correlation between MAO-B binding and age, and the effect of partial volume effect correction (PVEc) for the reproducibility were also estimated. %difference of k3 was 2.6% (medial frontal cortex) to 10.3% (hippocampus), and that of λk3 was 5.0% (thalamus) to 9.2% (cerebellum). Mean %difference of all regions were 5.3 and 7.0% in k3 and λk3, respectively. All regions showed below 10% variabilities except the hippocampus in k3 (10.3%). Intraclass correlation coefficient (ICC) of k3 was 0.78 (hippocampus) to 0.98 (medial frontal cortex), and that of λk3 was 0.78 (hippocampus) to 0.95 (thalamus). Mean ICC were 0.94 and 0.89 in k3 and λk3, respectively. The highest positive correlation with age was observed in the hippocampus, as ru2009=u20090.75 in k3 and 0.76 in λk3. After PVEc, mean %difference were 5.6 and 7.2% in k3 and λk3, respectively. Mean ICC were 0.92 and 0.90 for k3 and λk3, respectively. These values were almost the same as those before PVEc.ConclusionsThe present results indicate that k3 and λk3 of [11C]-l-deprenyl-D2 are reliable parameters for test-retest reproducibility with healthy subjects both before and after PVEc. The studies with patients of larger sample size are required for further clinical applications.

Characterization of [11C]PXT012253 as a PET Radioligand for mGlu4 Allosteric Modulators in Nonhuman Primates

PurposeModulation of presynaptic metabotropic glutamate receptor 4 (mGlu4) by an allosteric ligand has been proposed as a promising therapeutic target in Parkinson’s disease and levodopa-induced dyskinesia. A positron emission tomography (PET) ligand for an allosteric site of mGlu4 may provide evidence that a clinical drug candidate reaches and binds the target. A carbon-11-labeled PET radioligand binding an allosteric site of mGlu4, [11C]PXT012253, has been recently developed. Here, we describe the detailed characterization of this novel radiolabeled mGlu4 ligand in nonhuman primates.Procedures[11C]PXT012253 binding in the brain of cynomolgus monkeys, under the baseline and blocking conditions with the structurally different mGlu4 allosteric ligand PXT002331, currently in clinical trials for Parkinson’s disease, was quantified with compartment and graphical modeling approaches using a radiometabolite-corrected plasma input function. Whole-body biodistribution of [11C]PXT012253 was then assessed using PET/x-ray computed tomography to estimate the human effective doses of [11C]PXT012253 for further clinical studies.Results[11C]PXT012253 displayed binding in mGlu4-expressing regions in the brain of cynomolgus monkeys. Brain regional time-activity curves of [11C]PXT012253 were well described in the two-tissue compartment model (2TC). Total distribution volume was stably estimated using Logan plot and multilinear analysis (MA1) although 2TC showed unstable values in some cases. Competition with PXT002331 showed high specific binding in the total distribution volume. Whole-body PET showed high accumulation of [11C]PXT012253 in the liver, kidney, heart, and brain in the initial phase. The radioligand was excreted through both the gastrointestinal and the urinary tracts. Effective dose of [11C]PXT012253 was estimated to be 0.0042xa0mSv/MBq.Conclusions[11C]PXT012253 was shown to be a promising PET radioligand for mGlu4 allosteric modulators in the monkey brain. MA1 would be the choice of quantitative method. Further development of [11C]PXT012253 in human subjects is warranted.

Evidence of fatigue, disordered sleep and peripheral inflammation, but not increased brain TSPO expression, in seasonal allergy: A [ 11 C]PBR28 PET study

Allergy is associated with non-specific symptoms such as fatigue, sleep problems and impaired cognition. One explanation could be that the allergic inflammatory state includes activation of immune cells in the brain, but this hypothesis has not been tested in humans. The aim of the present study was therefore to investigate seasonal changes in the glial cell marker translocator protein (TSPO), and to relate this to peripheral inflammation, fatigue and sleep, in allergy. We examined 18 patients with severe seasonal allergy, and 13 healthy subjects in and out-of pollen season using positron emission tomography (nu202f=u202f15/13) and the TSPO radioligand [11C]PBR28. In addition, TNF-α, IL-5, IL-6, IL-8 and IFN-γ were measured in peripheral blood, and subjective ratings of fatigue and sleepiness as well as objective and subjective sleep were investigated. No difference in levels of TSPO was seen between patients and healthy subjects, nor in relation to pollen season. However, allergic subjects displayed both increased fatigue, sleepiness and increased percentage of deep sleep, as well as increased levels of IL-5 and TNF-α during pollen season, compared to healthy subjects. Allergic subjects also had shorter total sleep time, regardless of season. In conclusion, allergic subjects are indicated to respond to allergen exposure during pollen season with a clear pattern of behavioral disruption and peripheral inflammatory activation, but not with changes in brain TSPO levels. This underscores a need for development and use of more specific markers to understand brain consequences of peripheral inflammation that will be applicable in human subjects.

Revisiting the Logan plot to account for non-negligible blood volume in brain tissue

BackgroundReference tissue-based quantification of brain PET data does not typically include correction for signal originating from blood vessels, which is known to result in biased outcome measures. The bias extent depends on the amount of radioactivity in the blood vessels. In this study, we seek to revisit the well-established Logan plot and derive alternative formulations that provide estimation of distribution volume ratios (DVRs) that are corrected for the signal originating from the vasculature.ResultsNew expressions for the Logan plot based on arterial input function and reference tissue were derived, which included explicit terms for whole blood radioactivity. The new methods were evaluated using PET data acquired using [11C]raclopride and [18F]MNI-659. The two-tissue compartment model (2TCM), with which signal originating from blood can be explicitly modeled, was used as a gold standard.DVR values obtained for [11C]raclopride using the either blood-based or reference tissue-based Logan plot were systematically underestimated compared to 2TCM, and for [18F]MNI-659, a proportionality bias was observed, i.e., the bias varied across regions. The biases disappeared when optimal blood-signal correction was used for respective tracer, although for the case of [18F]MNI-659 a small but systematic overestimation of DVR was still observed.ConclusionsThe new method appears to remove the bias introduced due to absence of correction for blood volume in regular graphical analysis and can be considered in clinical studies. Further studies are however required to derive a generic mapping between plasma and whole-blood radioactivity levels.