Dataset Information

Development and Evaluation of [¹¹C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.

ABSTRACT: The paired bromodomains (BD1 and BD2), located in the bromodomain and extra-terminal (BET) family proteins, perform specific functions in gene transcriptional control and expression. Targeting specific bromodomains with inhibitors holds promise for achieving therapeutic benefits with reduced side effects. However, the comprehension of this target related to the disease is still restricted. Positron emission tomography (PET) imaging is a powerful tool that provides a valuable avenue for exploring the BD2 bromodomain. This investigation introduces a novel radioligand, [¹¹C]I-58, for PET targeting the BET BD2 domain. The synthesis of compound I-58, along with its radiosynthetic process for C11 labeling, is detailed, and the suitability of [¹¹C]I-58 for PET imaging of the BD2 bromodomain is evaluated. Initial PET study findings in mice indicate that [¹¹C]I-58 exhibits suitable biodistribution in peripheral organs and tissues. Additionally, in vitro autoradiography studies and blocking experiments provide compelling evidence supporting the specific binding of [¹¹C]I-58 to the BD2 bromodomain. These results establish [¹¹C]I-58 as a promising instrument for the PET imaging of the BD2 bromodomain. This research not only holds the potential to pave the path for developing PET radioligands precisely targeting the BD2 bromodomain but also adds to a more profound comprehension of the biological mechanisms linked to the BD bromodomain.

SUBMITTER: Wang Y

PROVIDER: S-EPMC11360046 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Development and Evaluation of [<sup>11</sup>C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.

Wang Yanli Y Wang Yongle Y Xu Yulong Y Tocci Darcy D Wang Changning C

ACS omega 20240812 34

The paired bromodomains (BD1 and BD2), located in the bromodomain and extra-terminal (BET) family proteins, perform specific functions in gene transcriptional control and expression. Targeting specific bromodomains with inhibitors holds promise for achieving therapeutic benefits with reduced side effects. However, the comprehension of this target related to the disease is still restricted. Positron emission tomography (PET) imaging is a powerful tool that provides a valuable avenue for exploring ...[more]

PMID: 39220497

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Project description:This was a first-in-human study of the PET radiotracer 11C-LSN3172176 for the muscarinic acetylcholine receptor subtype M1. The objectives of the study were to determine the appropriate kinetic model to quantify binding of the tracer to M1 receptors, and the reliability of the chosen quantification method. Methods: Six healthy subjects completed the test-retest protocol, and 5 healthy subjects completed the baseline-scopolamine blocking protocol. Multiple modeling methods were applied to calculate total distribution volume (V T) and nondisplaceable binding potential (BP ND) in various brain regions. The reference region was selected from the blocking study. The occupancy plot was applied to compute receptor occupancy by scopolamine and nondisplaceable distribution volume. Results: Tracer uptake was highest in the striatum, followed by neocortical regions and white matter, and lowest in the cerebellum. Regional time-activity curves were fitted well by all models. The 2-tissue-compartment (2TC) model fits were good, but the 2TC parameters often could not be reliably estimated. Because V T correlated well between the 2TC and 1-tissue-compartment (1TC) models after exclusion of unreliable estimates, the 1TC model was chosen as the most appropriate. The cerebellum showed the lowest V T, consistent with preclinical studies showing little to no specific binding in the region. Further, cerebellar V T did not change between baseline and blocking scans, indicating that the cerebellum is a suitable reference region. The simplified reference tissue model (SRTM) slightly underestimated 1TC BP ND, and the simplified reference tissue model 2 (SRTM2) improved BP ND estimation. An 80-min scan was sufficient to quantify V T and BP ND The test-retest study showed excellent absolute test-retest variability for 1TC V T (≤5%) and BP ND (≤10%). In the baseline and blocking studies, occupancy values were lower in the striatum than in nonstriatal regions, as may be attributed to differences in regional acetylcholine concentrations. Conclusion: The 1TC and SRTM2 models are appropriate for quantitative analysis of 11C-LSN3172176 imaging data. 11C-LSN3172176 displayed excellent test-retest reproducibility and is a highly promising ligand to quantify M1 receptors in the human brain.

Dataset Information

Development and Evaluation of [¹¹C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.

Publications

Development and Evaluation of [<sup>11</sup>C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.

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Dataset Information

Development and Evaluation of [11C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.

Publications

Development and Evaluation of [&lt;sup&gt;11&lt;/sup&gt;C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Development and Evaluation of [¹¹C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.

Development and Evaluation of [<sup>11</sup>C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.