[<sup>111</sup>In]In/[<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 SST<sub>2</sub>R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results
Aiming to expand the application of the SST<sub>2</sub>R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH<sub>2</sub>) beyond [<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>-LM4 PET/CT (DATA<sup>5m</sup>, (6-pentanoic acid)-6-(amino)me...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/3/776 |
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| author | Berthold A. Nock Panagiotis Kanellopoulos Euy Sung Moon Maritina Rouchota George Loudos Sanjana Ballal Madhav P. Yadav Chandrasekhar Bal Prashant Mishra Parvind Sheokand Frank Roesch Theodosia Maina |
| author_facet | Berthold A. Nock Panagiotis Kanellopoulos Euy Sung Moon Maritina Rouchota George Loudos Sanjana Ballal Madhav P. Yadav Chandrasekhar Bal Prashant Mishra Parvind Sheokand Frank Roesch Theodosia Maina |
| author_sort | Berthold A. Nock |
| collection | DOAJ |
| description | Aiming to expand the application of the SST<sub>2</sub>R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH<sub>2</sub>) beyond [<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>-LM4 PET/CT (DATA<sup>5m</sup>, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA<sup>5</sup>-LM4 (AAZTA<sup>5</sup>, 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine), allowing for the convenient coordination of trivalent radiometals of clinical interest, such as In-111 (for SPECT/CT) or Lu-177 (for radionuclide therapy). After labeling, the preclinical profiles of [<sup>111</sup>In]In-AAZTA<sup>5</sup>-LM4 and [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 were compared in HEK293-SST<sub>2</sub>R cells and double HEK293-SST<sub>2</sub>R/wtHEK293 tumor-bearing mice using [<sup>111</sup>In]In-DOTA-LM3 and [<sup>177</sup>Lu]Lu-DOTA-LM3 as references. The biodistribution of [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 was additionally studied for the first time in a NET patient. Both [<sup>111</sup>In]In-AAZTA<sup>5</sup>-LM4 and [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 displayed high and selective targeting of the HEK293-SST<sub>2</sub>R tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 in the patient according to SPECT/CT results in a monitoring time span of 4–72 h pi. In view of the above, we may conclude that [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 shows promise as a therapeutic radiopharmaceutical candidate for SST<sub>2</sub>R-expressing human NETs, based on previous [<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>-LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [<sup>111</sup>In]In-AAZTA<sup>5</sup>-LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available. |
| first_indexed | 2024-03-11T06:01:57Z |
| format | Article |
| id | doaj.art-2f0690fde7c64c7fa0a01549ebc2a9b7 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T06:01:57Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-2f0690fde7c64c7fa0a01549ebc2a9b72023-11-17T13:14:13ZengMDPI AGPharmaceutics1999-49232023-02-0115377610.3390/pharmaceutics15030776[<sup>111</sup>In]In/[<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 SST<sub>2</sub>R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient ResultsBerthold A. Nock0Panagiotis Kanellopoulos1Euy Sung Moon2Maritina Rouchota3George Loudos4Sanjana Ballal5Madhav P. Yadav6Chandrasekhar Bal7Prashant Mishra8Parvind Sheokand9Frank Roesch10Theodosia Maina11Molecular Radiopharmacy, INRaSTES, NCSR “Demokritos”, 15310 Athens, GreeceMolecular Radiopharmacy, INRaSTES, NCSR “Demokritos”, 15310 Athens, GreeceDepartment Chemie, Standort TRIGA, Johannes Gutenberg-Universität Mainz, D-55126 Mainz, GermanyBIOEMTECH, Lefkippos Attica Technology Park, NCSR “Demokritos”, 15310 Athens, GreeceBIOEMTECH, Lefkippos Attica Technology Park, NCSR “Demokritos”, 15310 Athens, GreeceDepartment of Nuclear Medicine, AIIMS, Ansari Nagar, New Delhi 110029, IndiaDepartment of Nuclear Medicine, AIIMS, Ansari Nagar, New Delhi 110029, IndiaDepartment of Nuclear Medicine, AIIMS, Ansari Nagar, New Delhi 110029, IndiaDepartment of Nuclear Medicine, AIIMS, Ansari Nagar, New Delhi 110029, IndiaDepartment of Nuclear Medicine, AIIMS, Ansari Nagar, New Delhi 110029, IndiaDepartment Chemie, Standort TRIGA, Johannes Gutenberg-Universität Mainz, D-55126 Mainz, GermanyMolecular Radiopharmacy, INRaSTES, NCSR “Demokritos”, 15310 Athens, GreeceAiming to expand the application of the SST<sub>2</sub>R-antagonist LM4 (DPhe-c[DCys-4Pal-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH<sub>2</sub>) beyond [<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>-LM4 PET/CT (DATA<sup>5m</sup>, (6-pentanoic acid)-6-(amino)methy-1,4-diazepinetriacetate), we now introduce AAZTA<sup>5</sup>-LM4 (AAZTA<sup>5</sup>, 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine), allowing for the convenient coordination of trivalent radiometals of clinical interest, such as In-111 (for SPECT/CT) or Lu-177 (for radionuclide therapy). After labeling, the preclinical profiles of [<sup>111</sup>In]In-AAZTA<sup>5</sup>-LM4 and [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 were compared in HEK293-SST<sub>2</sub>R cells and double HEK293-SST<sub>2</sub>R/wtHEK293 tumor-bearing mice using [<sup>111</sup>In]In-DOTA-LM3 and [<sup>177</sup>Lu]Lu-DOTA-LM3 as references. The biodistribution of [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 was additionally studied for the first time in a NET patient. Both [<sup>111</sup>In]In-AAZTA<sup>5</sup>-LM4 and [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 displayed high and selective targeting of the HEK293-SST<sub>2</sub>R tumors in mice and fast background clearance via the kidneys and the urinary system. This pattern was reproduced for [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 in the patient according to SPECT/CT results in a monitoring time span of 4–72 h pi. In view of the above, we may conclude that [<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 shows promise as a therapeutic radiopharmaceutical candidate for SST<sub>2</sub>R-expressing human NETs, based on previous [<sup>68</sup>Ga]Ga-DATA<sup>5m</sup>-LM4 PET/CT, but further studies are needed to fully assess its clinical value. Furthermore, [<sup>111</sup>In]In-AAZTA<sup>5</sup>-LM4 SPECT/CT may represent a legitimate alternative diagnostic option in cases where PET/CT is not available.https://www.mdpi.com/1999-4923/15/3/776somatostatin subtype 2 receptor (SST<sub>2</sub>R)-antagonistAAZTA<sup>5</sup> chelatorAAZTA<sup>5</sup>-LM4theranosticsneuroendocrine tumorsIn-111 |
| spellingShingle | Berthold A. Nock Panagiotis Kanellopoulos Euy Sung Moon Maritina Rouchota George Loudos Sanjana Ballal Madhav P. Yadav Chandrasekhar Bal Prashant Mishra Parvind Sheokand Frank Roesch Theodosia Maina [<sup>111</sup>In]In/[<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 SST<sub>2</sub>R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results Pharmaceutics somatostatin subtype 2 receptor (SST<sub>2</sub>R)-antagonist AAZTA<sup>5</sup> chelator AAZTA<sup>5</sup>-LM4 theranostics neuroendocrine tumors In-111 |
| title | [<sup>111</sup>In]In/[<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 SST<sub>2</sub>R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results |
| title_full | [<sup>111</sup>In]In/[<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 SST<sub>2</sub>R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results |
| title_fullStr | [<sup>111</sup>In]In/[<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 SST<sub>2</sub>R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results |
| title_full_unstemmed | [<sup>111</sup>In]In/[<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 SST<sub>2</sub>R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results |
| title_short | [<sup>111</sup>In]In/[<sup>177</sup>Lu]Lu-AAZTA<sup>5</sup>-LM4 SST<sub>2</sub>R-Antagonists in Cancer Theranostics: From Preclinical Testing to First Patient Results |
| title_sort | sup 111 sup in in sup 177 sup lu lu aazta sup 5 sup lm4 sst sub 2 sub r antagonists in cancer theranostics from preclinical testing to first patient results |
| topic | somatostatin subtype 2 receptor (SST<sub>2</sub>R)-antagonist AAZTA<sup>5</sup> chelator AAZTA<sup>5</sup>-LM4 theranostics neuroendocrine tumors In-111 |
| url | https://www.mdpi.com/1999-4923/15/3/776 |
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