Ana M. Catafau

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.

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.

Pharmacokinetics and time-course of D2 receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients

The 123I-IBZM SPECT measured D2 receptor occupancy (D2RO) in chronically dosed, stabilized schizophrenic patients and its relationship with antipsychotic (AP) pharmacokinetics (PK) over time is still unclear. The aims of this study were: 1) To define the relationship between striatal D2 receptor occupancy (D 2RO) and plasma concentration (C P) in stabilized schizophrenic patients on clinically relevant doses using 123I-IBZM SPECT; 2) To investigate the time course of AP-induced D2RO and corresponding C P. Forty-six schizophrenic patients on their clinically required doses of risperidone, olanzapine, clozapine or quetiapine were included. D 2RO and C P were measured over time following a sparse-sampling experimental design, and individual PK and D2RO-time profiles were estimated using a population approach. Observed striatal D2RO and C P ranges were 28—75% and 9.4—60.5 ng/mL for risperidone, 22—84% and 8.6—89.5 ng/mL for olanzapine, 5—53% and 41.6—818.2 ng/mL for clozapine and 0—64% and 37.9—719.6 ng/mL for quetiapine. A PK—D2RO relationship was found for the four APs. D2RO pattern over time was stable for risperidone, olanzapine and clozapine but fluctuating for quetiapine. Stabilized schizophrenic patients show a wide range of both D2RO and C P at clinically effective doses of the four AP, suggesting that clinical response to these AP may be maintained with D2RO below 65%. D2RO patterns over time differ between AP. These results should be considered for accurate interpretation of D2RO measurements, proper design of studies and optimization of drug regimens for patients on AP treatment.

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 scatter correction on D2 receptor occupancy measurements using 123I-IBZM SPECT: comparison to 11C-Raclopride PET.

Reported values of D(2) receptor occupancy (RO) achieved by antipsychotic drugs tend to be lower when measured with (123)I-IBZM SPECT than with (11)C-Raclopride PET. Image degrading factors such as attenuation, distance-dependent collimator response and scatter could account for this difference. While attenuation correction is routinely applied to SPECT images, the other degradations are not usually accounted for. The aim of this work was to assess the impact of scatter correction on D(2) RO quantification with (123)I-IBZM SPECT, and to compare the results of both corrected and un-corrected SPECT values with (11)C-Raclopride PET measurements. Phantom experiments as well as within-subject human data from a previous study were used for this purpose. SPECT images were reconstructed using filtered back-projection including attenuation correction (FBP(A)), ordered subsets expectation maximization including attenuation and point spread function corrections (OSEM(A+PSF)) and ordered subsets expectation maximization including attenuation, point spread function and scatter corrections (OSEM(A+PSF+SCT)). PET images were reconstructed using the FBP algorithm and corrected for attenuation, scatter, random coincidences and dead time. Quantification of receptor availability was performed using the tissue ratio at pseudoequilibrium for SPECT, and the simplified reference tissue model (SRTM) for PET. Analysis was performed using both occipital cortex (occ) and cerebellum (cer) as reference regions for both modalities. When images were reconstructed using FBP(A), SPECT D(2) RO values were significantly lower as compared with PET leading to a D(2) RO difference of -20% (CI(95%): -13, -27%) (occ) and -23% (CI(95%): -14, -31%) (cer). When images were reconstructed using OSEM(A+PSF), SPECT D(2) RO values were also lower as compared with PET leading to a D(2) RO difference of -21% (CI(95%): -14, -27%) (occ) and -24% (CI(95%): -18, -30%) (cer). When images were reconstructed using OSEM(A+PSF+SCT), the D(2) RO bias was reduced to -6% (CI(95%): 0, -13%) (occ) and -11% (CI(95%): -4, -18%) (cer). These data suggest that the scatter correction plays a major role in explaining the differences between D(2) RO measurements using (123)I-IBZM SPECT and (11)C-Raclopride PET.

Neurotransmission SPECT and MR registration combining mutual and gradient information.

Purpose: Image registration is important in functional image analysis. In neurotransmission single photon emission tomography (nSPECT), specific uptake sites can be accurately localized by superimposing the SPECT study onto a high-resolution structural image such as a magnetic resonance(MR) of the subject. Mutual-information (MI)-based algorithms are usually employed for this purpose. Nevertheless, nSPECT/MR registration using MI is often limited by the low count rates present in nSPECT. Several works have proposed extensions of the MI measures to include gradient information (GI) from the images but their performance has not been evaluated in SPECT studies. Methods: In this work, the accuracy of the MI including gradient information (MIG) was compared with the standard MI using data from healthy volunteers and data simulating a specific uptake reduction using three different radioligands: I 123 -IBZM , I 123 -ADAM , I 123 -R 91150 . Results: The results showed that MIG-based registration yielded better accuracy than MI. The MIG-based similarity measures were less sensitive to sparse sampling and diminished computational time without a substantial decrease in registration accuracy. Conclusions: Accuracy of nSPECT/MR registration is improved when gradient information is included in the MI-based algorithm, which makes MIG-based registration potentially useful for clinical applications.

A pseudo-reference region method applied to measurement of GlyT1 occupancy in human brain using [11C]GSK931145 and PET

Introduction: [11C]GSK931145 is a novel PET radiotracer for the glycine transporter type 1 (GlyT1), with promising characteristics in preclinical species (1). A human test–retest study in 10 healthy human volunteers produced poor test–retest statistics, with mean coefficient of variation (COV) of volume of distribution (VT; 2 tissue compartmental model) ∼21% in the regions with highest signal (brain stem, thalamus, and cerebellum). A similar high variability was seen in a subsequent study which explored GlyT1 occupancy by a novel GlyT1 antagonist GSK1018921 in 10 healthy volunteers. The occupancy plot method (2) was used to analyse the VT data, but failed to produce reliable estimates for 11 out of 20 post-dose scans. Major components of the VT variability in man were related to variability in the plasma input function and reduced brain uptake (3). A reference region method could offer an improvement, however, since GlyT1 is expressed throughout the brain no reference region was available. A pseudo reference region (PRR) method was developed to address the variability associated with the blood measures and the lack of a true reference region.

Absence of reference region: Is there a way to improve neuroreceptor occupancy quantification?

Objectives: Drug-induced neuroreceptor occupancy is usually estimated in positron emission tomography (PET) studies as the relative reduction of the non-displaceable binding potential. This binding potential might be estimated from the total and the non-displaceable (VND) volumes of distribution. However, a reference region with negligible specific binding, needed to estimate VND, might be unavailable. An occupancy plot has been proposed to estimate occupancy in these cases, though it has been shown to have a positive bias (Cunningham et al. 2009). The aim of this study was to investigate fitting methods that may lead to an improvement in the efficiency of occupancy plot estimates.

Functional Brain Imaging and Drug Development

The development of drugs for psychiatric diseases is a specially risky business, for several reasons: first, the etiology of most psychiatric diseases is unknown; second, most psychiatric diseases are exclusively human; and third, animal models are often limited or nonexistent. Usually large multicentric clinical trials are required to demonstrate clinical efficacy of a drug, with large investments and time needed. Functional brain imaging may help to decrease both time and investment in this process, thus becoming a useful tool for pharmaceutical companies. PET and SPECT are unique tools for the study of neurotransmission in humans in vivo, and allow direct assessment of the drug-target interactions at the synaptic level. Cerebral perfusion and metabolism imaging can indirectly contribute to drug development by allowing investigation of pathophysiology or the anatomical pathways implicated in psychiatric diseases and identification of the cerebral areas whose activity is modified as a consequence of drug administration. Functional brain imaging can be useful from very early stages of drug development, such as target identification. Furthermore, these techniques provide essential information on the pharmacokinetics and pharmacodynamics of the drug in the brain, contributing to the demonstration of the mechanism of action of the drugs and to the drug dosage. Small animal imaging systems are an additional tool, which together with neuroimaging of genetic expression in the future will help to complete the picture of functional brain imaging applications to drug development in Psychiatry.