Daniel Gündel, Mudasir Maqbool, Rodrigo Teodoro, Friedrich-Alexander Ludwig, Anne Heerklotz, Magali Toussaint, Winnie Deuther-Conrad, Guy Bormans, Peter Brust, Klaus Kopka, Rareş-Petru Moldovan
{"title":"氘化[18F]JHU94620同位素物用于脑内大麻素2型受体无创评估的研制与评价","authors":"Daniel Gündel, Mudasir Maqbool, Rodrigo Teodoro, Friedrich-Alexander Ludwig, Anne Heerklotz, Magali Toussaint, Winnie Deuther-Conrad, Guy Bormans, Peter Brust, Klaus Kopka, Rareş-Petru Moldovan","doi":"10.1186/s41181-024-00319-2","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>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 [<sup>18</sup>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 -<i>d</i><sub>4</sub> and -<i>d</i><sub>8</sub> deuterated isotopologues of [<sup>18</sup>F]JHU94620.</p><h3>Results</h3><p>The deuterated [<sup>18</sup>F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with <i>K</i><sub>D</sub> values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [<sup>18</sup>F]JHU94620-<i>d</i><sub>8</sub> in the spleen and to a local <i>h</i>CB2R(D80N) protein overexpression in the striatal region in rats.</p><h3>Conclusion</h3><p>These results support further investigations of [<sup>18</sup>F]JHU94620-<i>d</i><sub>8</sub> in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.4000,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00319-2","citationCount":"0","resultStr":"{\"title\":\"Development and evaluation of deuterated [18F]JHU94620 isotopologues for the non-invasive assessment of the cannabinoid type 2 receptor in brain\",\"authors\":\"Daniel Gündel, Mudasir Maqbool, Rodrigo Teodoro, Friedrich-Alexander Ludwig, Anne Heerklotz, Magali Toussaint, Winnie Deuther-Conrad, Guy Bormans, Peter Brust, Klaus Kopka, Rareş-Petru Moldovan\",\"doi\":\"10.1186/s41181-024-00319-2\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>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 [<sup>18</sup>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 -<i>d</i><sub>4</sub> and -<i>d</i><sub>8</sub> deuterated isotopologues of [<sup>18</sup>F]JHU94620.</p><h3>Results</h3><p>The deuterated [<sup>18</sup>F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with <i>K</i><sub>D</sub> values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [<sup>18</sup>F]JHU94620-<i>d</i><sub>8</sub> in the spleen and to a local <i>h</i>CB2R(D80N) protein overexpression in the striatal region in rats.</p><h3>Conclusion</h3><p>These results support further investigations of [<sup>18</sup>F]JHU94620-<i>d</i><sub>8</sub> in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation.</p></div>\",\"PeriodicalId\":534,\"journal\":{\"name\":\"EJNMMI Radiopharmacy and Chemistry\",\"volume\":\"9 1\",\"pages\":\"\"},\"PeriodicalIF\":4.4000,\"publicationDate\":\"2024-12-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00319-2\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"EJNMMI Radiopharmacy and Chemistry\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://link.springer.com/article/10.1186/s41181-024-00319-2\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, INORGANIC & NUCLEAR\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"EJNMMI Radiopharmacy and Chemistry","FirstCategoryId":"1085","ListUrlMain":"https://link.springer.com/article/10.1186/s41181-024-00319-2","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, INORGANIC & NUCLEAR","Score":null,"Total":0}
Development and evaluation of deuterated [18F]JHU94620 isotopologues for the non-invasive assessment of the cannabinoid type 2 receptor in brain
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 [18F]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 -d4 and -d8 deuterated isotopologues of [18F]JHU94620.
Results
The deuterated [18F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with KD values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [18F]JHU94620-d8 in the spleen and to a local hCB2R(D80N) protein overexpression in the striatal region in rats.
Conclusion
These results support further investigations of [18F]JHU94620-d8 in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation.
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