Ascending single-dose study of the safety, pharmacokinetics, and pharmacodynamics of CSTI-500, a novel monoamine triple reuptake inhibitor, first-in-human.

Rationale: Monoamine triple reuptake inhibitors (TRIs) inhibit central dopamine, norepinephrine, and serotonin transporters, restoring functional monoamine neurotransmission.

Objectives: This clinical trial evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after single-ascending-doses (SAD) of the novel monoamine TRI CSTI-500. In addition, we estimated the peak and duration of striatal serotonin transporter (SERT) and dopamine transporter (DAT) occupancies, by using positron emission tomography (PET).

Impact of image reconstruction on cerebral blood flow measured with O-water positron emission tomography.

Background: O-water positron emission tomography (PET) is considered the gold standard method for non-invasive measurement of cerebral blood flow (CBF). However, previously published average CBF values in healthy subjects have varied greatly and the cause of these variations remains unclear. This study investigates how image reconstruction methods and spatial resolution affect CBF measurements with O-water PET.

Quantitation of mitral regurgitation using positron emission tomography.

Background: Cardiac positron emission tomography (PET) offers non-invasive assessment of perfusion and left ventricular (LV) function from a single dynamic scan. However, no prior assessment of mitral regurgitation severity by PET has been presented. Application of indicator dilution techniques and gated image analyses to PET data enables calculation of forward stroke volume and total LV stroke volume.

Evaluation of [C]UCB-A positron emission tomography in human brains.

Background: In preclinical studies, the positron emission tomography (PET) imaging with [C]UCB-A provided promising results for imaging synaptic vesicle protein 2A (SV2A) as a proxy for synaptic density. This paper reports the first-in-human [C]UCB-A PET study to characterise its kinetics in healthy subjects and further evaluate SV2A-specific binding.

Results: Twelve healthy subjects underwent 90-min baseline [C]UCB-A scans with PET/MRI, with two subjects participating in an additional blocking scan with the same scanning procedure after a single dose of levetiracetam (1500 mg).

Comparison of quantitative [C]PE2I brain PET studies between an integrated PET/MR and a stand-alone PET system.

PET/MR systems demanded great efforts for accurate attenuation correction (AC) but differences in technology, geometry and hardware attenuation may also affect quantitative results. Dedicated PET systems using transmission-based AC are regarded as the gold standard for quantitative brain PET. The study aim was to investigate the agreement between quantitative PET outcomes from a PET/MR scanner against a stand-alone PET system.

Striatal dopamine transporter and receptor availability correlate with relative cerebral blood flow measured with [C]PE2I, [F]FE-PE2I and [C]raclopride PET in healthy individuals.

The aim of this retrospective study was to investigate relationships between relative cerebral blood flow and striatal dopamine transporter and dopamine D2/3 availability in healthy subjects. The data comprised dynamic PET scans with two dopamine transporter tracers [C]PE2I (n = 20) and [F]FE-PE2I (n = 20) and the D2/3 tracer [C]raclopride (n = 18). Subjects with a [C]PE2I scan also underwent a dynamic scan with the serotonin transporter tracer [C]DASB.

Image-derived input functions from dynamic O-water PET scans using penalised reconstruction.

Background: Quantitative positron emission tomography (PET) scans of the brain typically require arterial blood sampling but this is complicated and logistically challenging. One solution to remove the need for arterial blood sampling is the use of image-derived input functions (IDIFs). Obtaining accurate IDIFs, however, has proved to be challenging, mainly due to the limited resolution of PET.

Composite attenuation correction method using a Ge-transmission multi-atlas for quantitative brain PET/MR.

In positron emission tomography (PET), Ge-transmission scanning is considered the gold standard in attenuation correction (AC) though not available in current dual imaging systems. In this experimental study we evaluated a novel AC method for PET/magnetic resonance (MR) imaging which is essentially based on a composite database of multiple Ge-transmission maps and T1-weighted (T1w) MR image-pairs (composite transmission, CTR-AC). This proof-of-concept study used retrospectively a database with 125 pairs of co-registered Ge-AC maps and T1w MR images from anatomical normal subjects and a validation dataset comprising dynamic [C]PE2I PET data from nine patients with Parkinsonism.

Evaluation of Arterial Spin Labeling MRI-Comparison with O-Water PET on an Integrated PET/MR Scanner.

Cerebral blood flow (CBF) measurements are of high clinical value and can be acquired non-invasively with no radiation exposure using pseudo-continuous arterial spin labeling (ASL). The aim of this study was to evaluate accordance in resting state CBF between ASL (CBF) and O-water positron emission tomography (PET) (CBF) acquired simultaneously on an integrated 3T PET/MR system. The data comprised ASL and dynamic O-water PET data with arterial blood sampling of eighteen subjects (eight patients with focal epilepsy and ten healthy controls, age 21 to 61 years).

Cerebral blood flow measurements with O-water PET using a non-invasive machine-learning-derived arterial input function.

Cerebral blood flow (CBF) can be measured with dynamic positron emission tomography (PET) of O-labeled water by using tracer kinetic modelling. However, for quantification of regional CBF, an arterial input function (AIF), obtained from arterial blood sampling, is required. In this work we evaluated a novel, non-invasive approach for input function prediction based on machine learning (MLIF), against AIF for CBF PET measurements in human subjects.

Accuracy and precision of zero-echo-time, single- and multi-atlas attenuation correction for dynamic [C]PE2I PET-MR brain imaging.

Background: A valid photon attenuation correction (AC) method is instrumental for obtaining quantitatively correct PET images. Integrated PET/MR systems provide no direct information on attenuation, and novel methods for MR-based AC (MRAC) are still under investigation. Evaluations of various AC methods have mainly focused on static brain PET acquisitions.

Evaluation of zero-echo-time attenuation correction for integrated PET/MR brain imaging-comparison to head atlas and Ge-transmission-based attenuation correction.

Background: MRI does not offer a direct method to obtain attenuation correction maps as its predecessors (stand-alone PET and PET/CT), and bone visualisation is particularly challenging. Recently, zero-echo-time (ZTE) was suggested for MR-based attenuation correction (AC). The aim of this work was to evaluate ZTE- and atlas-AC by comparison to Ge-transmission scan-based AC.

Association between amygdala neurokinin-1 receptor availability and anxiety-related personality traits.

Animal studies indicate that substance P (SP) and its preferred neurokinin-1 (NK1) receptor modulate stress and anxiety-related behavior. Alterations in the SP-NK1 system have also been observed in human anxiety disorders, yet little is known about the relation between this system and individual differences in personality traits associated with anxiety propensity and approach-avoidance behavior, including trait anxiety, neuroticism, and extraversion. Exploring this relation could provide important insights into the neurobiological underpinnings of human anxiety and the etiology of anxiety disorders, as anxious traits are associated with increased susceptibility to develop psychopathological conditions.

Development of a clinically feasible [C]PE2I PET method for differential diagnosis of parkinsonism using reduced scan duration and automated reference region extraction.

[C]PE2I is a highly selective dopamine transporter PET ligand. Parametric images based on dynamic [C]PE2I scans, showing dopamine transporter availability (BP) and relative cerebral blood flow (R), can be used in differential diagnosis of parkinsonism. This work aimed to investigate a shortened scan duration and automated generation of parametric images which are two prerequisites for routine clinical application.

Visualization of painful inflammation in patients with pain after traumatic ankle sprain using [C]-D-deprenyl PET/CT.

Background And Aims: Positron emission tomography (PET) with the radioligand [C]-D-deprenyl has shown increased signal at location of pain in patients with rheumatoid arthritis and chronic whiplash injury. The binding site of [C]-D-deprenyl in peripheral tissues is suggested to be mitochondrial monoamine oxidase in cells engaged in post-traumatic inflammation and tissue repair processes. The association between [C]-D-deprenyl uptake and the transition from acute to chronic pain remain unknown.

Decreased Brain Neurokinin-1 Receptor Availability in Chronic Tennis Elbow.

Substance P is released in painful and inflammatory conditions, affecting both peripheral processes and the central nervous system neurokinin 1 (NK1) receptor. There is a paucity of data on human brain alterations in NK1 expression, how this system may be affected by treatment, and interactions between central and peripheral tissue alterations. Ten subjects with chronic tennis elbow (lateral epicondylosis) were selected out of a larger (n = 120) randomized controlled trial evaluating graded exercise as a treatment for chronic tennis elbow (lateral epicondylosis).

Reduced serotonin synthesis and regional cerebral blood flow after anxiolytic treatment of social anxiety disorder.

Social anxiety disorder (SAD) is associated with increased fear-related neural activity in the amygdala and we recently found enhanced serotonin synthesis rate in the same region. Anxiolytic agents like selective serotonin re-uptake inhibitors (SSRIs) and neurokinin-1 receptor (NK1R) antagonists reduce amygdala activity and may attenuate serotonin formation according to animal studies. Here, we examined the effects of SSRI pharmacotherapy, NK1R antagonism, and placebo on serotonin synthesis rate in relation to neural activity, measured as regional cerebral blood flow (rCBF), and symptom improvement in SAD.

Serotonin synthesis rate and the tryptophan hydroxylase-2: G-703T polymorphism in social anxiety disorder.

It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[β -(11)C]tryptophan, [(11)C]5-HTP, a substrate of the second enzymatic step in serotonin synthesis.

Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.

Importance: Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively.

Objective: To examine the serotonin synthesis rate and serotonin transporter availability in patients with SAD and healthy control individuals using positron emission tomography (PET) with the radioligands 5-hydroxytryptophan labeled with carbon 11 ([11C]5-HTP) and 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [11C]DASB.

Use of 11C-PE2I PET in differential diagnosis of parkinsonian disorders.

Unlabelled: In idiopathic Parkinson disease and atypical parkinsonian disorders, central dopaminergic and overall brain functional activity are altered to different degrees, causing difficulties in achieving an unambiguous clinical diagnosis. A dual examination using (123)I-FP-CIT ((123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane, or (123)I-ioflupane) SPECT and(18)F-FDG PET provides complementary information on dopamine transporter (DAT) availability and overall brain functional activity, respectively. Parametric images based on a single, dynamic (11)C-PE2I (N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methyl-phenyl)nortropane) scan potentially supply both DAT availability (nondisplaceable binding potential [BPND]) and relative cerebral blood flow (relative delivery [R1]) at voxel level.

Safety, pharmacokinetic, and positron emission tomography evaluation of serotonin and dopamine transporter occupancy following multiple-dose administration of the triple monoamine reuptake inhibitor BMS-820836.

Rationale: BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine.

Objective: This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [(11)C]MADAM or [(11)C]PE2I, respectively.

Amygdala-frontal couplings characterizing SSRI and placebo response in social anxiety disorder.

Unlabelled: In patients with social anxiety disorder (SAD) it has been reported that selective serotonin reuptake inhibitors (SSRIs) and placebo induce anxiolytic effects by attenuating neural activity in overlapping amygdala subregions, i.e. left basolateral and right ventrolateral amygdala.

Tesofensine, a novel triple monoamine re-uptake inhibitor with anti-obesity effects: dopamine transporter occupancy as measured by PET.

Tesofensine (TE) is a novel triple monoamine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [¹¹C]βCIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days.

PET-scan shows peripherally increased neurokinin 1 receptor availability in chronic tennis elbow: visualizing neurogenic inflammation?

Unlabelled: In response to pain, neurokinin 1 (NK1) receptor availability is altered in the central nervous system. The NK1 receptor and its primary agonist, substance P, also play a crucial role in peripheral tissue in response to pain, as part of neurogenic inflammation. However, little is known about alterations in NK1 receptor availability in peripheral tissue in chronic pain conditions and very few studies have been performed on human beings.

Validation of parametric methods for [¹¹C]PE2I positron emission tomography.

Objectives: The radioligand [(11)C]PE2I is highly selective for dopamine transporter (DAT) and can be used in vivo for investigation of changes in DAT concentration, progression of disease and validation of treatment using positron emission tomography (PET). DAT is an important protein for regulation of central dopamine concentration and DAT deficiency has been associated with several neurodegenerative and neuropsychiatric disorders. Accurate parametric images are a prerequisite for clinical application of [(11)C]PE2I.