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用于脑内大麻素2型受体无创评估的氘代[F]JHU94620同位素类似物的研发与评价

Development and evaluation of deuterated [F]JHU94620 isotopologues for the non-invasive assessment of the cannabinoid type 2 receptor in brain.

作者信息

Gündel Daniel, Maqbool Mudasir, Teodoro Rodrigo, Ludwig Friedrich-Alexander, Heerklotz Anne, Toussaint Magali, Deuther-Conrad Winnie, Bormans Guy, Brust Peter, Kopka Klaus, Moldovan Rareş-Petru

机构信息

Department of Experimental Neurooncological Radiopharmacy, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Research Site Leipzig, Permoserstrasse 15, 04318, Leipzig, Germany.

Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892-1026, USA.

出版信息

EJNMMI Radiopharm Chem. 2024 Dec 23;9(1):91. doi: 10.1186/s41181-024-00319-2.

DOI:10.1186/s41181-024-00319-2
PMID:39714717
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11666850/
Abstract

BACKGROUND

The cannabinoid type 2 receptors (CB2R) represent a target of increasing importance in neuroimaging due to its upregulation under various neuropathological conditions. Previous evaluation of [F]JHU94620 for the non-invasive assessment of the CB2R availability by positron emission tomography (PET) revealed favourable binding properties and brain uptake, however rapid metabolism, and generation of brain-penetrating radiometabolites have been its main limitations. To reduce the bias of CB2R quantification by blood-brain barrier (BBB)-penetrating radiometabolites, we aimed to improve the metabolic stability by developing -d and -d deuterated isotopologues of [F]JHU94620.

RESULTS

The deuterated [F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with K values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [F]JHU94620-d in the spleen and to a local hCB2R(D80N) protein overexpression in the striatal region in rats.

CONCLUSION

These results support further investigations of [F]JHU94620-d in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation.

摘要

背景

2型大麻素受体（CB2R）在神经影像学中成为一个越来越重要的靶点，因为它在各种神经病理条件下会上调。先前通过正电子发射断层扫描（PET）对[F]JHU94620用于CB2R可用性的无创评估显示出良好的结合特性和脑摄取，但快速代谢以及产生可穿透血脑屏障的放射性代谢物一直是其主要局限性。为了减少可穿透血脑屏障的放射性代谢物对CB2R定量的偏差，我们旨在通过开发[F]JHU94620的 -d和 -d氘代同位素类似物来提高代谢稳定性。

结果

氘代[F]JHU94620同位素类似物显示出改善的代谢稳定性，避免了随着时间推移可穿透血脑屏障的放射性代谢物在脑中的积累。在不同物种中测定了CB2R特异性结合，其K值在低纳摩尔范围内。动态PET研究揭示了[F]JHU94620 -d在大鼠脾脏中的CB2R特异性和可逆摄取，以及在纹状体区域局部hCB2R（D80N）蛋白的过表达。

结论

这些结果支持在CB2R过表达的病理模型和组织中进一步研究[F]JHU94620 -d，作为临床转化的前提条件。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/cb34c9032346/41181_2024_319_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/b8e2b0e767be/41181_2024_319_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/51c59228a8f5/41181_2024_319_Sch2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/4b01abfc238d/41181_2024_319_Sch3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/bf86f7d9fa22/41181_2024_319_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/f0c7b3ec1856/41181_2024_319_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/a6a866efc148/41181_2024_319_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/6d6194b80aa3/41181_2024_319_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/cb34c9032346/41181_2024_319_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/b8e2b0e767be/41181_2024_319_Sch1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/51c59228a8f5/41181_2024_319_Sch2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/4b01abfc238d/41181_2024_319_Sch3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/bf86f7d9fa22/41181_2024_319_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/f0c7b3ec1856/41181_2024_319_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/a6a866efc148/41181_2024_319_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/6d6194b80aa3/41181_2024_319_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f888/11666850/cb34c9032346/41181_2024_319_Fig5_HTML.jpg

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