Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-Substance P
Radiopharmaceutical development hinges on the affinity and selectivity of the biological component for the intended target. An analogue of the neuropeptide Substance P (SP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/3/2134 |
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| author | Janine Suthiram Ané Pieters Zulfiah Mohamed Moosa Jan Rijn Zeevaart Mike M. Sathekge Thomas Ebenhan Ross C. Anderson Claire L. Newton |
| author_facet | Janine Suthiram Ané Pieters Zulfiah Mohamed Moosa Jan Rijn Zeevaart Mike M. Sathekge Thomas Ebenhan Ross C. Anderson Claire L. Newton |
| author_sort | Janine Suthiram |
| collection | DOAJ |
| description | Radiopharmaceutical development hinges on the affinity and selectivity of the biological component for the intended target. An analogue of the neuropeptide Substance P (SP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-SP (DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP), in the theranostic pair [<sup>68</sup>Ga]Ga-/ [<sup>213</sup>Bi]Bi-DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP has shown promising clinical results in the treatment of inoperable glioblastoma. As the theranostic targeting component, modifications to SP that affect the selectivity of the resulting analogue for the intended target (neurokinin-1 receptor [NK1R]) could be detrimental to its therapeutic potential. In addition to other closely related tachykinin receptors (neurokinin-2 receptor [NK2R] and neurokinin-3 receptor [NK3R]), SP can activate a mast cell expressed receptor Mas-related G protein-coupled receptor subtype 2 (MRGPRX2), which has been implicated in allergic-type reactions. Therefore, activation of these receptors by SP analogues has severe implications for their therapeutic potential. Here, the receptor selectivity of DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP was examined using inositol phosphate accumulation assay in HEK293-T cells expressing NK1R, NK2R, NK3R or MRGPRX2. DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP had similar efficacy and potency as native SP at NK1R, but displayed greater NK1R selectivity. DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP was unable to elicit significant activation of the other tachykinin receptors nor MRGPRX2 at high concentrations nor did it display antagonistic behaviour at these receptors. DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP, therefore has high potency and selectivity for NK1R, supporting its potential for targeted theranostic use in glioblastoma multiforme and other conditions characterised by NK1R overexpression. |
| first_indexed | 2024-03-11T09:43:09Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c2f02b93f82d44cd93f835ef7a5bdecf2023-11-16T16:52:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-01-01243213410.3390/ijms24032134Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-Substance PJanine Suthiram0Ané Pieters1Zulfiah Mohamed Moosa2Jan Rijn Zeevaart3Mike M. Sathekge4Thomas Ebenhan5Ross C. Anderson6Claire L. Newton7Department of Radiochemistry, The South African Nuclear Energy Corporation SOC Ltd. (Necsa), Brits 0240, South AfricaDepartment of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South AfricaDepartment of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South AfricaDepartment of Radiochemistry, The South African Nuclear Energy Corporation SOC Ltd. (Necsa), Brits 0240, South AfricaDepartment of Nuclear Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South AfricaDepartment of Nuclear Medicine, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South AfricaDepartment of Physiology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South AfricaCentre for Neuroendocrinology, Department of Immunology, Faculty of Health Sciences, University of Pretoria, Private Bag X323, Gezina 0031, South AfricaRadiopharmaceutical development hinges on the affinity and selectivity of the biological component for the intended target. An analogue of the neuropeptide Substance P (SP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-SP (DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP), in the theranostic pair [<sup>68</sup>Ga]Ga-/ [<sup>213</sup>Bi]Bi-DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP has shown promising clinical results in the treatment of inoperable glioblastoma. As the theranostic targeting component, modifications to SP that affect the selectivity of the resulting analogue for the intended target (neurokinin-1 receptor [NK1R]) could be detrimental to its therapeutic potential. In addition to other closely related tachykinin receptors (neurokinin-2 receptor [NK2R] and neurokinin-3 receptor [NK3R]), SP can activate a mast cell expressed receptor Mas-related G protein-coupled receptor subtype 2 (MRGPRX2), which has been implicated in allergic-type reactions. Therefore, activation of these receptors by SP analogues has severe implications for their therapeutic potential. Here, the receptor selectivity of DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP was examined using inositol phosphate accumulation assay in HEK293-T cells expressing NK1R, NK2R, NK3R or MRGPRX2. DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP had similar efficacy and potency as native SP at NK1R, but displayed greater NK1R selectivity. DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP was unable to elicit significant activation of the other tachykinin receptors nor MRGPRX2 at high concentrations nor did it display antagonistic behaviour at these receptors. DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP, therefore has high potency and selectivity for NK1R, supporting its potential for targeted theranostic use in glioblastoma multiforme and other conditions characterised by NK1R overexpression.https://www.mdpi.com/1422-0067/24/3/2134neurokinin-1 receptorneurokinin-2 receptorneurokinin-3 receptormas-related G protein-coupled receptor subtype 2receptor selectivityDOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP |
| spellingShingle | Janine Suthiram Ané Pieters Zulfiah Mohamed Moosa Jan Rijn Zeevaart Mike M. Sathekge Thomas Ebenhan Ross C. Anderson Claire L. Newton Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-Substance P International Journal of Molecular Sciences neurokinin-1 receptor neurokinin-2 receptor neurokinin-3 receptor mas-related G protein-coupled receptor subtype 2 receptor selectivity DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP |
| title | Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-Substance P |
| title_full | Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-Substance P |
| title_fullStr | Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-Substance P |
| title_full_unstemmed | Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-Substance P |
| title_short | Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]-Substance P |
| title_sort | tachykinin receptor selectivity of the potential glioblastoma targeted therapy dota thi sup 8 sup met o sub 2 sub sup 11 sup substance p |
| topic | neurokinin-1 receptor neurokinin-2 receptor neurokinin-3 receptor mas-related G protein-coupled receptor subtype 2 receptor selectivity DOTA-[Thi<sup>8</sup>,Met(O<sub>2</sub>)<sup>11</sup>]SP |
| url | https://www.mdpi.com/1422-0067/24/3/2134 |
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