Search

For radioligands without a reference region, the Lassen plot can be used to estimate receptor occupancy by an exogenous drug ( O Drug ). However, the Lassen plot is not well-suited for spatial variation in O Drug . To overcome this limitation, we introduce a Lassen plot filter, i.e. a Lassen plot applied to local neighborhoods in PET images. Image data were simulated with regional variation in V N D , O Drug , both, or neither and analyzed using the change in binding potential ( Δ B P N D ), the conventional Lassen plot, and the Lassen plot filter at the region of interest (ROI) and voxel level. All methods were also applied to a human [ 11 C]flumazenil occupancy study using PF-06372865. This combination of a non-selective radioligand and selective drug should lead to varying O Drug   provided the distribution of subtypes varies spatially. In contrast with Δ B P N D and the conventional Lassen plot, ROI-level and voxel-level Lassen plot filter estimates remained unbiased in the presence of regional variation in V N D or O Drug . In the [ 11 C]flumazenil data-set, O Drug was shown to vary regionally in accordance with the distribution of binding sites for [ 11 C]flumazenil and PF-06372865. We demonstrate that a local-neighborhood Lassen plot filter provides robust and unbiased estimates of O Drug and V N D without the need for any user intervention.

Studies in rodents suggest that flumazenil is a P-glycoprotein substrate at the blood-brain barrier. This study aimed to assess whether [ 11 C]flumazenil is a P-glycoprotein substrate in humans and to what extent increased P-glycoprotein function in epilepsy may confound interpretation of clinical [ 11 C]flumazenil studies used to assess gamma-aminobutyric acid A receptors. Nine drug-resistant patients with epilepsy and mesial temporal sclerosis were scanned twice using [ 11 C]flumazenil before and after partial P-glycoprotein blockade with tariquidar. Volume of distribution, nondisplaceable binding potential, and the ratio of rate constants of [ 11 C]flumazenil transport across the blood-brain barrier (K 1 /k 2 ) were derived for whole brain and several regions. All parameters were compared between pre- and post-tariquidar scans. Regional results were compared between mesial temporal sclerosis and contralateral sides. Tariquidar significantly increased global K 1 /k 2 (+23%) and volume of distribution (+10%), but not nondisplaceable binding potential. At the mesial temporal sclerosis side volume of distribution and nondisplaceable binding potential were lower in hippocampus (both ∼-19%) and amygdala (both ∼-16%), but K 1 /k 2 did not differ, suggesting that only regional gamma-aminobutyric acid A receptor density is altered in epilepsy. In conclusion, although [ 11 C]flumazenil appears to be a (weak) P-glycoprotein substrate in humans, this does not seem to affect its role as a tracer for assessing gamma-aminobutyric acid A receptor density., (© The Author(s) 2015.)

Benzodiazepines are effective short-term treatments for anxiety disorders, but their use is limited by undesirable side effects related to Central Nervous System impairment and tolerance development. SL65.1498 is a new compound that acts in vitro as a full agonist at the gamma-aminobutyric acid(A) 2 and 3 receptor and as a partial agonist at the 1 and 5 receptor subtypes. It is thought that the compound could be anxiolytic by its activation at the alpha2 and alpha3 receptor subtypes, without causing unfavourable side effects, which are believed to be mediated by the alpha1 and alpha5 subtypes. This study was a double-blind, five-way cross-over study to investigate the effects of three doses of SL65.1498 in comparison with placebo and lorazepam 2 mg in healthy volunteers. The objective was to select a dose level (expected to be therapeutically active), free of any significant deleterious effect. Psychomotor and cognitive effects were measured using a validated battery of measurements, including eye movements, body sway, memory tests, reaction-time assessments, and visual analogue scales. The highest dose of SL65.1498 showed slight effects on saccadic peak velocity and smooth pursuit performance, although to a much lesser extent than lorazepam. In contrast to lorazepam, none of the SL65.1498 doses affected body sway, visual analogue scale alertness, attention, or memory tests. This study showed that the three doses of SL65.1498 were well tolerated and induced no impairments on memory, sedation, psychomotor, and cognitive functions.

This article deals with the problem of model selection for the mathematical description of tracer kinetics in nuclear medicine. It stems from the consideration of some specific data sets where different models have similar performances. In these situations, it is shown that considerate averaging of a parameter's estimates over the entire model set is better than obtaining the estimates from one model only. Furthermore, it is also shown that the procedure of averaging over a small number of "good" models reduces the "generalization error," the error introduced when the model selected over a particular data set is applied to different conditions, such as subject populations with altered physiologic parameters, modified acquisition protocols, and different signal-to-noise ratios. The method of averaging over the entire model set uses Akaike coefficients as measures of an individual model's likelihood. To facilitate the understanding of these statistical tools, the authors provide an introduction to model selection criteria and a short technical treatment of Akaike's information-theoretic approach. The new method is illustrated and epitomized by a case example on the modeling of [11C]flumazenil kinetics in the brain, containing both real and simulated data.

The ability to study multiple physiologic processes of the brain simultaneously within the same subject would provide a new means to explore the interactions between neurotransmitter systems in vivo. Currently, examination of two distinct neuropharmacologic measures with positron emission tomography (PET) necessitates performing two separate scans spaced in time to allow for radionuclide decay. The authors present results from a dual-tracer PET study protocol using a single dynamic-scan acquisition where the injections of two tracers are offset by several minutes. Kinetic analysis is used to estimate neuropharmacologic parameters for both tracers simultaneously using a combined compartmental model configuration. This approach results in a large reduction in total study time of nearly 2 hours for carbon-11-labeled tracers. As multiple neuropharmacologic measures are obtained at nearly the same time, interventional protocols involving a pair of dual-tracer scans become feasible in a single PET session. Both computer simulations and actual human PET studies were performed using combinations of three different tracers: [11C]flumazenil, N-[11C]methylpiperidinyl propionate, and [ 11 C]dihydrotetrabenazine. Computer simulations of tracer-injection separations of 10 to 30 minutes showed the feasibility of the approach for separations down to 15 to 20 minutes or less. Dual-tracer PET studies were performed in 32 healthy volunteers using injection separations of 10, 15, or 20 minutes. Model parameter estimates for each tracer were similar to those obtained from previously performed single-injection studies. Voxel-by-voxel parametric images were of good quality for injections spaced by 20 minutes and were nearly as good for 15-minute separations, but were degraded noticeably for some model parameters when injections were spaced by only 10 minutes. The authors conclude that dual-tracer single-scan PET is feasible, yields accurate estimates of multiple neuropharmacologic measures, and can be implemented with a number of different radiotracer pairs.

Gamma-hydroxybutyrate (GHB) is a compound used in the treatment of alcohol withdrawal, narcolepsy, and for induction of anaesthesia. It is also contained in many products illegally marketed as "dietary supplements" and is increasingly being recognised as a potential drug of abuse. We report the case of a 44-year-old man who suffered coma and life-threatening respiratory depression following an accidental overdose of the GHB prodrug, gamma-butyrolactone (GBL), contained in a "health drink". He made a full recovery following appropriate supportive treatment. GHB toxicity should be included in the differential diagnosis of patients with altered mental state, particularly where there is a history of recreational drug abuse.

The calculated fraction of receptor ligands available for blood-brain barrier passage in vivo (f(avail)) may differ from in vitro (f(eq)) measurements. This study evaluates the protein-ligand interaction for iomazenil and flumazenil in rats by comparing f(eq) and f(avail). Repeated measurements of blood-brain barrier permeability for two benzodiazepine antagonists were performed in 44 rats by the double-indicator technique. Cerebral blood flow was measured by intracarotid Xe-injection. The apparent permeability-surface product (PSapp) was measured while CBF or bolus composition was changed. Comparison of PSapp obtained in the absence and presence of 5% albumin in the injectate yielded f(avail), whereas f(eq) was measured by equilibrium dialysis. Iomazenil and flumazenil f(avail) was 62% and 82%, respectively, whereas f(eq) was significantly lower, 42% and 61%. The PSapp for iomazenil and flumazenil increased significantly by 89% and 161% after relative CBF increases of 259% and 201%, respectively. The results demonstrate that application of f(eq) in neuroreceptor studies underestimates the plasma input function to the brain. Model simulations render possible that the differences between f(avail) and f(eq) as well as the effect of CBF on PSapp can be caused by capillary heterogeneity.

The in vivo quantification of the benzodiazepine receptor concentration in human brain using positron emission tomography (PET) and 11C-flumazenil (11C-FMZ), is usually based on a three-compartment model and on PET curves measured in a small number of large regions of interest; however, it should be interesting to estimate the receptor concentration for each pixel and to build quantified images of the receptor concentration. The main advantage is to allow screening of the receptor site localization and visual observation of the possible abnormalities. Up to now, all the methods described include complex experimental protocols, difficult to use in routine examinations. In this paper, we propose the partial-saturation approach to obtain parametric images of benzodiazepine receptor concentration and FMZ affinity. It consists of a single FMZ injection with a low specific activity, followed by Scatchard analysis. Like other parametric imaging methods, this partial-saturation approach can lead to a small percentage (< 1%) of unrealistic values in receptor-poor regions; however, it is the only method that allows receptor concentration and affinity images to be obtained from a single-injection 40-min experiment without blood sampling. We also propose a second method in which the receptor concentration map is directly deduced from the PET image acquired 5 to 10 min after a partial-saturation injection. This method assumes a known and constant FMZ affinity value but requires only very simple corrections of this PET image. It is robust (negative values are never found) and quite simple to use in routine examination of patients (no blood sampling, single injection, only 10-min experiment).