Dataset Information

Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET.

ABSTRACT: Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABAA receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action. In this work we investigated whether the proposed activity of clarithromycin at the GABAA receptor is associated with the benzodiazepine binding site using in vivo [(11)C]flumazenil positron emission tomography (PET) in primates and ex vivo [(3)H]flumazenil autoradiography in rat brain. While the studies demonstrate that clarithromycin does not change the K d of FMZ, nor does it competitively displace FMZ, there is preliminary evidence from the primate PET imaging studies that clarithromycin delays dissociation and washout of flumazenil from the primate brain in a dose-dependent fashion. These findings would be consistent with the proposed GABAA allosteric modulator function of clarithromycin. While the results are only preliminary, further investigation of the interaction of clarithromycin with GABA receptors and/or GABAergic medications is warranted, and therapeutic applications of clarithromycin alone or in combination with flumazenil, to treat hyper-GABAergic status in PD at minimally effective doses, should also be pursued.

SUBMITTER: Scott PJ

PROVIDER: S-EPMC4983726 | biostudies-other | 2016 Aug

REPOSITORIES: biostudies-other

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Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET.

Scott Peter J H PJ Shao Xia X Desmond Timothy J TJ Hockley Brian G BG Sherman Phillip P Quesada Carole A CA Frey Kirk A KA Koeppe Robert A RA Kilbourn Michael R MR Bohnen Nicolaas I NI

ACS medicinal chemistry letters 20160601 8

Clarithromycin is a potential treatment for hypersomnia acting through proposed negative allosteric modulation of GABAA receptors. We were interested whether this therapeutic benefit might extend to Parkinson's disease (PD) patients because GABAergic neurotransmission is implicated in postural control. Prior to initiating clinical studies in PD patients, we wished to better understand clarithromycin's mechanism of action. In this work we investigated whether the proposed activity of clarithromyc ...[more]

PMID: 27563397

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Project description:We used positron emission tomography imaging with [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)- benzonitrile (DASB) and principal component analysis to investigate whether a specific Parkinson's disease (PD)-related spatial covariance pattern could be identified for the serotonergic system. We also explored if non-manifesting leucine-rich repeat kinase 2 (LRRK2) mutation carriers, with normal striatal dopaminergic innervation as measured with [11C]-dihydrotetrabenazine (DTBZ), exhibit a distinct spatial covariance pattern compared to healthy controls and subjects with manifest PD. 15 subjects with sporadic PD, eight subjects with LRRK2 mutation-associated PD, nine LRRK2 non-manifesting mutation carriers, and nine healthy controls participated in the study. The analysis was applied to the DASB non-displaceable binding potential values evaluated in 42 pre-defined regions of interest. PD was found to be associated with a specific spatial covariance pattern, comprising relatively decreased DASB binding in the caudate, putamen and substantia nigra and relatively preserved binding in the hypothalamus and hippocampus; the expression of this pattern in PD subjects was significantly higher than in healthy controls (P < 0.001) and correlated significantly with disease duration (P < 0.01) and with DTBZ binding in the more affected putamen (P < 0.01). The LRRK2 non-manifesting mutation carriers expressed a different pattern, also significantly different from healthy controls (P < 0.001), comprising relatively decreased DASB binding in the pons, pedunculopontine nucleus, thalamus and rostral raphe nucleus, and with relatively preserved binding in the hypothalamus, amygdala, hippocampus and substantia nigra. This pattern was not present in either sporadic or LRRK2 mutation-associated PD subjects. These findings, although obtained with a relatively limited number of subjects, suggest that specific and overall distinct spatial serotonergic patterns may be associated with PD and LRRK2 mutations. Alterations in regions where relative upregulation is observed in both patterns may be indicative of compensatory mechanisms preceding or protecting from disease manifestation.

Project description:Combined positron emission tomography (PET) and magnetic resonance imaging (MRI) targeting the prostate-specific membrane antigen (PSMA) with a 68Ga-labelled PSMA-analog (68Ga-PSMA-11) is discussed as a promising diagnostic method for patients with suspicion or history of prostate cancer. One potential drawback of this method are severe photopenic (halo-) artifacts surrounding the bladder and the kidneys in the scatter-corrected PET images, which have been reported to occur frequently in clinical practice. The goal of this work was to investigate the occurrence and impact of these artifacts and, secondly, to evaluate variants of the standard scatter correction method with regard to halo-artifact suppression.Experiments using a dedicated pelvis phantom were conducted to investigate whether the halo-artifact is modality-, tracer-, and/or concentration-dependent. Furthermore, 31 patients with history of prostate cancer were selected from an ongoing 68Ga-PSMA-11-PET/MRI study. For each patient, PET raw data were reconstructed employing six different variants of PET scatter correction: absolute scatter scaling, relative scatter scaling, and relative scatter scaling combined with prompt gamma correction, each of which was combined with a maximum scatter fraction (MaxSF) of MaxSF = 75% or MaxSF = 40%. Evaluation of the reconstructed images with regard to halo-artifact suppression was performed both quantitatively using statistical analysis and qualitatively by two independent readers.The phantom experiments did not reveal any modality-dependency (PET/MRI vs. PET/CT) or tracer-dependency (68Ga vs. 18F-FDG). Patient- and phantom-based data indicated that halo-artifacts derive from high organ-to-background activity ratios (OBR) between bladder/kidneys and surrounding soft tissue, with a positive correlation between OBR and halo size. Comparing different variants of scatter correction, reducing the maximum scatter fraction from the default value MaxSF = 75% to MaxSF = 40% was found to efficiently suppress halo-artifacts in both phantom and patient data. In 1 of 31 patients, reducing the maximum scatter fraction provided new PET-based information changing the patient's diagnosis.Halo-artifacts are particularly observed for 68Ga-PSMA-11-PET/MRI due to 1) the biodistribution of the PSMA-11-tracer resulting in large OBRs for bladder and kidneys and 2) inaccurate scatter correction methods currently used in clinical routine, which tend to overestimate the scatter contribution. If not compensated for, 68Ga-PSMA-11 uptake pathologies may be masked by halo-artifacts leading to false-negative diagnoses. Reducing the maximum scatter fraction was found to efficiently suppress halo-artifacts.

Dataset Information

Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET.

Publications

Investigation of Proposed Activity of Clarithromycin at GABAA Receptors Using [(11)C]Flumazenil PET.

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