Balu Easwaramoorthy

Imaging Changes in Glutamate Transmission In Vivo with the Metabotropic Glutamate Receptor 5 Tracer [11C] ABP688 and N-Acetylcysteine Challenge

BACKGROUND An imaging method to probe glutamate levels in vivo would allow the study of glutamate transmission in disease states and in response to therapeutic interventions. Here we demonstrate the feasibility of this approach for the first time using positron emission tomography and [(11)C] ABP688, a radiotracer for an allosteric site on the metabotropic glutamate receptor 5. METHODS We conducted two sets of experiments in anesthetized baboons: test and retest without pharmacologic challenge and in combination with N-acetylcysteine (NAC), a promoter of the cystine-glutamate antiporter that increases extrasynaptic glutamate release. The goal was to assess whether NAC-induced changes in [(11)C] ABP688 binding potential, ΔBP(ND), could be detected above the noise in the measurement. RESULTS Linear mixed modeling comparing ΔBP(ND) from test-retest to ΔBP(ND) from NAC challenge across all brain regions showed a highly significant effect of treatment [F(1,40) = 21.2, p < .001]. ΔBP(ND) was significantly different from zero following NAC [F(1,20) = 76.6, p < .001] but not after test-retest studies. CONCLUSIONS NAC induced decrease in [(11)C] ABP688 ΔBP(ND) may be the result of allosteric modulation, although other mechanisms may be at play. We outline steps needed to replicate and validate this method as a new tool to measure in vivo glutamate transmission.

In vivo binding of antipsychotics to D3 and D2 receptors: a PET study in baboons with [11C]-(+)-PHNO.

Measuring the in vivo occupancy of antipsychotic drugs at dopamine D2 and D3 receptors separately has been difficult because of the lack of selective radiotracers. The recently developed [11C]-(+)-PHNO is D3-preferring, allowing estimates of the relative D2 and D3 binding of antipsychotic drugs. We used positron emission tomography (PET) imaging in baboons with [11C]-(+)-PHNO to examine the binding of clozapine and haloperidol to D2 and D3 receptors. Four animals were scanned with dynamically acquired PET and arterial plasma input functions. Test and retest scans were acquired in single scanning sessions for three subjects to assess the reproducibility of [11C]-(+)-PHNO scans. Four additional scans were acquired in each of three subjects following single doses of antipsychotic drugs (clozapine 0.5534 mg/kg, haloperidol 0.0109 mg/kg, two administrations per drug per subject) and compared with baseline scans. The percent change in binding (ΔBPND) following challenges with antipsychotic drugs was measured. A regression model, based on published values of regional D2 and D3 fractions of [11C]-(+)-PHNO BPND in six brain regions, was used to infer occupancy at D2 and D3 receptors. BPND following antipsychotic challenge decreased in all regions. Estimated D2 : D3 selectivity was 2.38 for haloperidol and 5.25 for clozapine, similar to published in vitro values for haloperidol (3.03), but slightly higher for clozapine (2.82). These data suggest that acute doses of clozapine and haloperidol bind to D3 receptors in vivo, and that the lack of D3 occupancy by antipsychotics observed in some recent imaging studies may be because of other phenomena.

In vivo binding of antipsychotics to D3 and D2 receptors

Measuring the in vivo occupancy of antipsychotic drugs at dopamine D2 and D3 receptors separately has been difficult because of the lack of selective radiotracers. The recently developed [11C]-(+)-PHNO is D3-preferring, allowing estimates of the relative D2 and D3 binding of antipsychotic drugs. We used positron emission tomography (PET) imaging in baboons with [11C]-(+)-PHNO to examine the binding of clozapine and haloperidol to D2 and D3 receptors. Four animals were scanned with dynamically acquired PET and arterial plasma input functions. Test and retest scans were acquired in single scanning sessions for three subjects to assess the reproducibility of [11C]-(+)-PHNO scans. Four additional scans were acquired in each of three subjects following single doses of antipsychotic drugs (clozapine 0.5534 mg/kg, haloperidol 0.0109 mg/kg, two administrations per drug per subject) and compared with baseline scans. The percent change in binding (ΔBPND) following challenges with antipsychotic drugs was measured. A regression model, based on published values of regional D2 and D3 fractions of [11C]-(+)-PHNO BPND in six brain regions, was used to infer occupancy at D2 and D3 receptors. BPND following antipsychotic challenge decreased in all regions. Estimated D2 : D3 selectivity was 2.38 for haloperidol and 5.25 for clozapine, similar to published in vitro values for haloperidol (3.03), but slightly higher for clozapine (2.82). These data suggest that acute doses of clozapine and haloperidol bind to D3 receptors in vivo, and that the lack of D3 occupancy by antipsychotics observed in some recent imaging studies may be because of other phenomena.

Characterization of in vivo pharmacological properties and sensitivity to endogenous serotonin of [11C] P943: A positron emission tomography study in Papio anubis

[11C] P943 is a recently developed PET radiotracer for serotonin 5‐HT1B receptors. We characterized a number of its in vivo pharmacokinetic properties, including the evaluation of its two stereo‐isomers, saturability of specific binding, selectivity for 5‐HT1B and 5‐HT1D receptors, and vulnerability to pharmacologically induced increases in endogenous 5‐HT levels. Six isoflurane‐anesthetized baboons were scanned with [11C] P943 at baseline, and following various pharmacological manipulations. The interventions included the administration of pharmacological doses of P943, SB‐616234‐S (a 5‐HT1B selective antagonist), SB‐714786 (a 5‐HT1D selective antagonist), as well as the administration of 5‐HT releasing agents (fenfluramine, amphetamine) and 5‐HT reuptake inhibitor (citalopram). [11C] P943 was observed to bind saturably and specifically to 5‐HT1B receptors and to be sensitive to all three challenges known to alter 5‐HT levels in the proximity of receptors. [11C] P943 shows promise as a tracer to image serotonin function in healthy subjects as well as subjects with psychiatric or neurologic conditions. Synapse, 2011.

Reproducibility and sensitivity to pharmacological challenge of [11C]-ABP688 in non-human primate brain

Purpose: 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-C-methyl-oxime ([C]-ABP688) is a highly-selective antagonist PET tracer for imaging the metabotropic glutamate receptor subtype 5 (mGluR5). The aims of this study were to test the reproducibility of outcome measures using this tracer with anesthetized baboons and to test the effect of challenge with the glutamate releaser N-acetylcysteine (NAC) on [C]-ABP688 specific binding.