A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11
Abstract Background The current generation of radiolabeled PSMA-targeting therapeutic agents is limited by prominent salivary gland binding, which results in dose-limiting xerostomia from radiation exposure. JB-1498 is a urea-based small molecule with a highly negatively charged linker targeting pro...
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
SpringerOpen
2024-01-01
|
Series: | EJNMMI Radiopharmacy and Chemistry |
Subjects: | |
Online Access: | https://doi.org/10.1186/s41181-024-00237-3 |
_version_ | 1797272776354037760 |
---|---|
author | Steve S. Huang Frank P. DiFilippo Daniel J. Lindner Warren D. Heston |
author_facet | Steve S. Huang Frank P. DiFilippo Daniel J. Lindner Warren D. Heston |
author_sort | Steve S. Huang |
collection | DOAJ |
description | Abstract Background The current generation of radiolabeled PSMA-targeting therapeutic agents is limited by prominent salivary gland binding, which results in dose-limiting xerostomia from radiation exposure. JB-1498 is a urea-based small molecule with a highly negatively charged linker targeting prostate specific membrane antigen (PSMA). Prior work on a similar tracer with the same negatively charged linker demonstrated low normal organ/soft tissue background uptake compared to [68Ga]Ga-PSMA-11. The purpose of this study was to investigate if [68Ga]Ga-JB-1498 had reduced salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11. Results JB-1498 demonstrated high affinity for PSMA binding and tumor uptake in a murine tumor model. In an initial biodistribution study with low molar activity, [68Ga]Ga-JB-1498 demonstrated salivary gland uptake of 0.13 ± 0.01%ID/g. In a second biodistribution study in non-tumor-bearing mice with high molar activity, [68Ga]Ga-JB1498 demonstrated salivary gland uptake of 0.39 ± 0.24% ID/g and kidney activity of 10.12 ± 1.73% ID/g at one hour post IV injection. This salivary gland uptake is significantly less than the published uptake of [68Ga]Ga-PSMA-11. Micro-PET visually confirmed the findings of the biodistribution studies. Dynamic micro-PET imaging demonstrated gradually decreasing [68Ga]Ga-JB1498 activity in salivary glands and kidneys, compared to gradually increasing [68Ga]Ga-PSMA-11 activity in these two organs during the first hour. Conclusion Biodistribution and micro-PET imaging of [68Ga]Ga-JB-1498 demonstrate significantly decreased salivary gland uptake and different pharmacokinetic behavior in kidneys and salivary glands in mice compared to [68Ga]Ga-PSMA-11. Our findings suggest that constructing a PSMA-targeting molecule with a highly negatively charged linker is a promising strategy to reduce salivary gland uptake of GCP-II/PSMA ligands in theranostic applications. |
first_indexed | 2024-03-07T14:34:13Z |
format | Article |
id | doaj.art-a2cf72a7ba264a219fd6e22305160176 |
institution | Directory Open Access Journal |
issn | 2365-421X |
language | English |
last_indexed | 2024-03-07T14:34:13Z |
publishDate | 2024-01-01 |
publisher | SpringerOpen |
record_format | Article |
series | EJNMMI Radiopharmacy and Chemistry |
spelling | doaj.art-a2cf72a7ba264a219fd6e223051601762024-03-05T20:46:10ZengSpringerOpenEJNMMI Radiopharmacy and Chemistry2365-421X2024-01-01911810.1186/s41181-024-00237-3A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11Steve S. Huang0Frank P. DiFilippo1Daniel J. Lindner2Warren D. Heston3Cleveland ClinicCleveland ClinicCleveland ClinicCleveland ClinicAbstract Background The current generation of radiolabeled PSMA-targeting therapeutic agents is limited by prominent salivary gland binding, which results in dose-limiting xerostomia from radiation exposure. JB-1498 is a urea-based small molecule with a highly negatively charged linker targeting prostate specific membrane antigen (PSMA). Prior work on a similar tracer with the same negatively charged linker demonstrated low normal organ/soft tissue background uptake compared to [68Ga]Ga-PSMA-11. The purpose of this study was to investigate if [68Ga]Ga-JB-1498 had reduced salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11. Results JB-1498 demonstrated high affinity for PSMA binding and tumor uptake in a murine tumor model. In an initial biodistribution study with low molar activity, [68Ga]Ga-JB-1498 demonstrated salivary gland uptake of 0.13 ± 0.01%ID/g. In a second biodistribution study in non-tumor-bearing mice with high molar activity, [68Ga]Ga-JB1498 demonstrated salivary gland uptake of 0.39 ± 0.24% ID/g and kidney activity of 10.12 ± 1.73% ID/g at one hour post IV injection. This salivary gland uptake is significantly less than the published uptake of [68Ga]Ga-PSMA-11. Micro-PET visually confirmed the findings of the biodistribution studies. Dynamic micro-PET imaging demonstrated gradually decreasing [68Ga]Ga-JB1498 activity in salivary glands and kidneys, compared to gradually increasing [68Ga]Ga-PSMA-11 activity in these two organs during the first hour. Conclusion Biodistribution and micro-PET imaging of [68Ga]Ga-JB-1498 demonstrate significantly decreased salivary gland uptake and different pharmacokinetic behavior in kidneys and salivary glands in mice compared to [68Ga]Ga-PSMA-11. Our findings suggest that constructing a PSMA-targeting molecule with a highly negatively charged linker is a promising strategy to reduce salivary gland uptake of GCP-II/PSMA ligands in theranostic applications.https://doi.org/10.1186/s41181-024-00237-3PSMAGCP-IIProstate cancerSalivary gland toxicity |
spellingShingle | Steve S. Huang Frank P. DiFilippo Daniel J. Lindner Warren D. Heston A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11 EJNMMI Radiopharmacy and Chemistry PSMA GCP-II Prostate cancer Salivary gland toxicity |
title | A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11 |
title_full | A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11 |
title_fullStr | A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11 |
title_full_unstemmed | A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11 |
title_short | A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11 |
title_sort | novel psma targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to 68ga ga psma 11 |
topic | PSMA GCP-II Prostate cancer Salivary gland toxicity |
url | https://doi.org/10.1186/s41181-024-00237-3 |
work_keys_str_mv | AT steveshuang anovelpsmatargetingtracerwithhighlynegativelychargedlinkerdemonstratesdecreasedsalivaryglanduptakeinmicecomparedto68gagapsma11 AT frankpdifilippo anovelpsmatargetingtracerwithhighlynegativelychargedlinkerdemonstratesdecreasedsalivaryglanduptakeinmicecomparedto68gagapsma11 AT danieljlindner anovelpsmatargetingtracerwithhighlynegativelychargedlinkerdemonstratesdecreasedsalivaryglanduptakeinmicecomparedto68gagapsma11 AT warrendheston anovelpsmatargetingtracerwithhighlynegativelychargedlinkerdemonstratesdecreasedsalivaryglanduptakeinmicecomparedto68gagapsma11 AT steveshuang novelpsmatargetingtracerwithhighlynegativelychargedlinkerdemonstratesdecreasedsalivaryglanduptakeinmicecomparedto68gagapsma11 AT frankpdifilippo novelpsmatargetingtracerwithhighlynegativelychargedlinkerdemonstratesdecreasedsalivaryglanduptakeinmicecomparedto68gagapsma11 AT danieljlindner novelpsmatargetingtracerwithhighlynegativelychargedlinkerdemonstratesdecreasedsalivaryglanduptakeinmicecomparedto68gagapsma11 AT warrendheston novelpsmatargetingtracerwithhighlynegativelychargedlinkerdemonstratesdecreasedsalivaryglanduptakeinmicecomparedto68gagapsma11 |