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Separating dopamine D₂ and D₃ receptor sources of [¹¹C]-(+)-PHNO binding potential: Independent component analysis of competitive binding.

ABSTRACT: 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 (BP_ND) images were analyzed as four-dimensional image series using ICA to extract two independent sources of variation in [¹¹C]-(+)-PHNO BP_ND. 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.

SUBMITTER: Smart K

PROVIDER: S-EPMC7263955 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Dopamine type 2 and type 3 receptors (D2R/D3R) appear critical to addictive disorders. Cocaine-use disorder (CUD) is associated with lower D2R availability and greater D3R availability in regions primarily expressing D2R or D3R concentrations, respectively. However, these CUD-related alterations in D2R and D3R have not been concurrently detected using available dopaminergic radioligands. Furthermore, receptor availability in regions of mixed D2R/D3R concentration in CUD remains unclear. The current study aimed to extend investigations of CUD-related alterations in D2R and D3R availability using regional and source-based analyses of [11C]-(+)-PHNO positron emission tomography (PET) of 26 individuals with CUD and 26 matched healthy comparison (HC) participants. Regional analysis detected greater binding potential (BPND) in CUD in the midbrain, consistent with prior [11C]-(+)-PHNO research, and lower BPND in CUD in the dorsal striatum, consistent with research using non-selective D2R/D3R radiotracers. Exploratory independent component analysis (ICA) identified three sources of BPND (striatopallidal, pallidonigral, and mesoaccumbens sources) that represent systems of brain regions displaying coherent variation in receptor availability. The striatopallidal source was associated with estimates of regional D2R-related proportions of BPND (calculated using independent reports of [11C]-(+)-PHNO receptor binding fractions), was lower in intensity in CUD and negatively associated with years of cocaine use. By comparison, the pallidonigral source was associated with estimates of regional D3R distribution, was greater in intensity in CUD and positively associated with years of cocaine use. The current study extends previous D2R/D3R research in CUD, demonstrating both lower BPND in the D2R-rich dorsal striatum and greater BPND in the D3R-rich midbrain using a single radiotracer. In addition, exploratory ICA identified sources of [11C]-(+)-PHNO BPND that were correlated with regional estimates of D2R-related and D3R-related proportions of BPND, were consistent with regional differences in CUD, and suggest receptor alterations in CUD may also be present in regions of mixed D2R/D3R concentration.

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Separating dopamine D₂ and D₃ receptor sources of [¹¹C]-(+)-PHNO binding potential: Independent component analysis of competitive binding.

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Dataset Information

Separating dopamine D2 and D3 receptor sources of [11C]-(+)-PHNO binding potential: Independent component analysis of competitive binding.

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OmicsDI is part of the ELIXIR infrastructure

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Separating dopamine D₂ and D₃ receptor sources of [¹¹C]-(+)-PHNO binding potential: Independent component analysis of competitive binding.