Toward Stability Enhancement of NTS<sub>1</sub>R-Targeted Radioligands: Structural Interventions on [<sup>99m</sup>Tc]Tc-DT1
The neurotensin subtype 1 receptor (NTS<sub>1</sub>R) is overexpressed in a number of human tumors, thereby representing a valid target for cancer theranostics with radiolabeled neurotensin (NT) analogs like [<sup>99m</sup>Tc]Tc-DT1 (DT1, N<sub>4</sub>-Gly<sup&...
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MDPI AG
2023-08-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/8/2092 |
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| author | Panagiotis Kanellopoulos Berthold A. Nock Eric P. Krenning Theodosia Maina |
| author_facet | Panagiotis Kanellopoulos Berthold A. Nock Eric P. Krenning Theodosia Maina |
| author_sort | Panagiotis Kanellopoulos |
| collection | DOAJ |
| description | The neurotensin subtype 1 receptor (NTS<sub>1</sub>R) is overexpressed in a number of human tumors, thereby representing a valid target for cancer theranostics with radiolabeled neurotensin (NT) analogs like [<sup>99m</sup>Tc]Tc-DT1 (DT1, N<sub>4</sub>-Gly<sup>7</sup>-NT(8-13)). Thus far, the fast degradation of intravenously injected NT–radioligands by neprilysin (NEP) and angiotensin-converting enzyme (ACE) has compromised their clinical applicability. Aiming at metabolic stability enhancements, we herein introduce (i) DT7 ([DAsn<sup>14</sup>]DT1) and (ii) DT8 ([β-Homoleucine<sup>13</sup>]DT1), modified at the C-terminus, along with (iii) DT9 ([(palmitoyl)Lys<sup>7</sup>]DT1), carrying an albumin-binding domain (ABD) at Lys<sup>7</sup>. The biological profiles of the new [<sup>99m</sup>Tc]Tc–radioligands were compared with [<sup>99m</sup>Tc]Tc-DT1, using NTS<sub>1</sub>R-expressing AsPC-1 cells and mice models without or during NEP/ACE inhibition. The radioligands showed enhanced in vivo stability vs. [<sup>99m</sup>Tc]Tc-DT1, with [<sup>99m</sup>Tc]Tc-DT9 displaying full resistance to both peptidases. Furthermore, [<sup>99m</sup>Tc]Tc-DT9 achieved the highest cell internalization and tumor uptake even without NEP/ACE-inhibition but with unfavorably high background radioactivity levels. Hence, unlike C-terminal modification, the introduction of a pendant ABD group in the linker turned out to be the most promising strategy toward metabolic stability, cell uptake, and tumor accumulation of [<sup>99m</sup>Tc]Tc-DT1 mimics. To improve the observed suboptimal pharmacokinetics of [<sup>99m</sup>Tc]Tc-DT9, the replacement of palmitoyl on Lys<sup>7</sup> by other ABD groups is currently being pursued. |
| first_indexed | 2024-03-10T23:39:21Z |
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| id | doaj.art-3463a33f5dd0475b8b34fef879e407fa |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T23:39:21Z |
| publishDate | 2023-08-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-3463a33f5dd0475b8b34fef879e407fa2023-11-19T02:36:41ZengMDPI AGPharmaceutics1999-49232023-08-01158209210.3390/pharmaceutics15082092Toward Stability Enhancement of NTS<sub>1</sub>R-Targeted Radioligands: Structural Interventions on [<sup>99m</sup>Tc]Tc-DT1Panagiotis Kanellopoulos0Berthold A. Nock1Eric P. Krenning2Theodosia Maina3Molecular Radiopharmacy, INRaSTES, NCSR “Demokritos”, 15341 Athens, GreeceMolecular Radiopharmacy, INRaSTES, NCSR “Demokritos”, 15341 Athens, GreeceCyclotron Rotterdam BV, Erasmus MC, 3015 CE Rotterdam, The NetherlandsMolecular Radiopharmacy, INRaSTES, NCSR “Demokritos”, 15341 Athens, GreeceThe neurotensin subtype 1 receptor (NTS<sub>1</sub>R) is overexpressed in a number of human tumors, thereby representing a valid target for cancer theranostics with radiolabeled neurotensin (NT) analogs like [<sup>99m</sup>Tc]Tc-DT1 (DT1, N<sub>4</sub>-Gly<sup>7</sup>-NT(8-13)). Thus far, the fast degradation of intravenously injected NT–radioligands by neprilysin (NEP) and angiotensin-converting enzyme (ACE) has compromised their clinical applicability. Aiming at metabolic stability enhancements, we herein introduce (i) DT7 ([DAsn<sup>14</sup>]DT1) and (ii) DT8 ([β-Homoleucine<sup>13</sup>]DT1), modified at the C-terminus, along with (iii) DT9 ([(palmitoyl)Lys<sup>7</sup>]DT1), carrying an albumin-binding domain (ABD) at Lys<sup>7</sup>. The biological profiles of the new [<sup>99m</sup>Tc]Tc–radioligands were compared with [<sup>99m</sup>Tc]Tc-DT1, using NTS<sub>1</sub>R-expressing AsPC-1 cells and mice models without or during NEP/ACE inhibition. The radioligands showed enhanced in vivo stability vs. [<sup>99m</sup>Tc]Tc-DT1, with [<sup>99m</sup>Tc]Tc-DT9 displaying full resistance to both peptidases. Furthermore, [<sup>99m</sup>Tc]Tc-DT9 achieved the highest cell internalization and tumor uptake even without NEP/ACE-inhibition but with unfavorably high background radioactivity levels. Hence, unlike C-terminal modification, the introduction of a pendant ABD group in the linker turned out to be the most promising strategy toward metabolic stability, cell uptake, and tumor accumulation of [<sup>99m</sup>Tc]Tc-DT1 mimics. To improve the observed suboptimal pharmacokinetics of [<sup>99m</sup>Tc]Tc-DT9, the replacement of palmitoyl on Lys<sup>7</sup> by other ABD groups is currently being pursued.https://www.mdpi.com/1999-4923/15/8/2092neurotensin subtype 1 receptorradiolabeled neurotensintargeted tumor imagingTc-99mmetabolic stabilityneprilysin |
| spellingShingle | Panagiotis Kanellopoulos Berthold A. Nock Eric P. Krenning Theodosia Maina Toward Stability Enhancement of NTS<sub>1</sub>R-Targeted Radioligands: Structural Interventions on [<sup>99m</sup>Tc]Tc-DT1 Pharmaceutics neurotensin subtype 1 receptor radiolabeled neurotensin targeted tumor imaging Tc-99m metabolic stability neprilysin |
| title | Toward Stability Enhancement of NTS<sub>1</sub>R-Targeted Radioligands: Structural Interventions on [<sup>99m</sup>Tc]Tc-DT1 |
| title_full | Toward Stability Enhancement of NTS<sub>1</sub>R-Targeted Radioligands: Structural Interventions on [<sup>99m</sup>Tc]Tc-DT1 |
| title_fullStr | Toward Stability Enhancement of NTS<sub>1</sub>R-Targeted Radioligands: Structural Interventions on [<sup>99m</sup>Tc]Tc-DT1 |
| title_full_unstemmed | Toward Stability Enhancement of NTS<sub>1</sub>R-Targeted Radioligands: Structural Interventions on [<sup>99m</sup>Tc]Tc-DT1 |
| title_short | Toward Stability Enhancement of NTS<sub>1</sub>R-Targeted Radioligands: Structural Interventions on [<sup>99m</sup>Tc]Tc-DT1 |
| title_sort | toward stability enhancement of nts sub 1 sub r targeted radioligands structural interventions on sup 99m sup tc tc dt1 |
| topic | neurotensin subtype 1 receptor radiolabeled neurotensin targeted tumor imaging Tc-99m metabolic stability neprilysin |
| url | https://www.mdpi.com/1999-4923/15/8/2092 |
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