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Association of dopamine D_2/3 receptor binding potential measured using PET and [¹¹C]-(+)-PHNO with post-mortem DRD_2/3 gene expression in the human brain.

ABSTRACT: Open access post-mortem transcriptome atlases such as the Allen Human Brain Atlas (AHBA) can inform us about mRNA expression of numerous proteins of interest across the whole brain, while in vivo protein binding in the human brain can be quantified by means of neuroreceptor positron emission tomography (PET). By combining both modalities, the association between regional gene expression and receptor distribution in the living brain can be approximated. Here, we compare the characteristics of D₂ and D₃ dopamine receptor distribution by applying the dopamine D_2/3 receptor agonist radioligand [¹¹C]-(+)-PHNO and human gene expression data. Since [¹¹C]-(+)-PHNO has a higher affinity for D₃ compared to D₂ receptors, we hypothesized that there is a stronger relationship between D_2/3 non-displaceable binding potentials (BP_ND) and D₃ mRNA expression. To investigate the relationship between D_2/3 BP_ND and mRNA expression of DRD2 and DRD3 we performed [¹¹C]-(+)-PHNO PET scans in 27 healthy subjects (12 females) and extracted gene expression data from the AHBA. We also calculated D₂/D₃ mRNA expression ratios to imitate the mixed D_2/3 signal of [¹¹C]-(+)-PHNO. In accordance with our a priori hypothesis, a strong correlation between [¹¹C]-(+)-PHNO and DRD3 expression was found. However, there was no significant correlation with DRD2 expression. Calculated D₂/D₃ mRNA expression ratios also showed a positive correlation with [¹¹C]-(+)-PHNO binding, reflecting the mixed D_2/3 signal of the radioligand. Our study supports the usefulness of combining gene expression data from open access brain atlases with in vivo imaging data in order to gain more detailed knowledge on neurotransmitter signaling.

SUBMITTER: Komorowski A

PROVIDER: S-EPMC7610745 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Development of medications selective for dopamine D2 or D3 receptors is an active area of research in numerous neuropsychiatric disorders including addiction and Parkinson's disease. The positron emission tomography (PET) radiotracer [11C]-(+)-PHNO, an agonist that binds with high affinity to both D2 and D3 receptors, has been used to estimate relative receptor subtype occupancy by drugs based on a priori knowledge of regional variation in the expression of D2 and D3 receptors. The objective of this work was to use a data-driven independent component analysis (ICA) of receptor blocking scans to separate D2-and D3-related signal in [11C]-(+)-PHNO binding data in order to improve the precision of subtype specific measurements of binding and occupancy. Eight healthy volunteers underwent [11C]-(+)-PHNO PET scans at baseline and at two time points following administration of the D3-preferring antagonist ABT-728 (150-1000 mg). Parametric binding potential (BPND) images were analyzed as four-dimensional image series using ICA to extract two independent sources of variation in [11C]-(+)-PHNO BPND. Spatial source maps for each component were consistent with respective regional patterns of D2-and D3-related binding. ICA-derived occupancy estimates from each component were similar to D2-and D3-specific occupancy estimated from a region-based approach (intraclass correlation coefficients > 0.95). ICA-derived estimates of D3 receptor occupancy improved quality of fit to a single site binding model. Furthermore, ICA-derived estimates of the regional fraction of [11C]-(+)-PHNO binding related to D3 receptors was generated for each subject and values showed good agreement with region-based model estimates and prior literature values. In summary, ICA successfully separated D2-and D3-related components of the [11C]-(+)-PHNO binding signal, establishing this approach as a powerful data-driven method to quantify distinct biological features from PET data composed of mixed data sources.

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Association of dopamine D_2/3 receptor binding potential measured using PET and [¹¹C]-(+)-PHNO with post-mortem DRD_2/3 gene expression in the human brain.

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Association of dopamine D2/3 receptor binding potential measured using PET and [11C]-(+)-PHNO with post-mortem DRD2/3 gene expression in the human brain.

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OmicsDI is part of the ELIXIR infrastructure

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Association of dopamine D_2/3 receptor binding potential measured using PET and [¹¹C]-(+)-PHNO with post-mortem DRD_2/3 gene expression in the human brain.