biostudies-literatureAbouzayed AVetenskapsrådetSwedish Cancer Foundation1221103https://www.ebi.ac.uk/biostudies/studies/S-EPMC10565663biostudies-literatureUnknown13<h4>Introduction</h4>Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression <i>in vivo</i> using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that ¹⁷⁷Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy.<h4>Methods</h4>BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [¹⁷⁷Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution <i>in vivo</i>, target specificity and dosimetry. [¹⁷⁷Lu]Lu-PSMA-617 was simultaneously evaluated for comparison.<h4>Results</h4>BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific <i>in vitro</i> and <i>in vivo</i> when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [¹⁷⁷Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities K_D1 = 3.8 nM and K_D2 = 25 nM. The half-maximal inhibitory concentration for ^natLu-BQ7876 was 59 nM that is equal to 61 nM for ^natLu-PSMA-617. Cellular processing of [¹⁷⁷Lu]Lu-BQ7876 was accompanied by slow internalization. [¹⁷⁷Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3%ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen.<h4>Discussion</h4>Biodistribution studies in mice demonstrated that targeting properties of [¹⁷⁷Lu]Lu-BQ7876 are not inferior to properties of [¹⁷⁷Lu]Lu-PSMA-617, but do not offer any decisive advantages.Frontiers in oncology¹⁷⁷Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry.PMC1056566320-0815 PjF2019-00986Abouzayed ASeitova KLundmark FOrlova ATolmachev VBodenko VRosenstrom UOroujeni Mfalse¹⁷⁷Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry.<h4>Introduction</h4>Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression <i>in vivo</i> using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that ¹⁷⁷Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy.<h4>Methods</h4>BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [¹⁷⁷Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution <i>in vivo</i>, target specificity and dosimetry. [¹⁷⁷Lu]Lu-PSMA-617 was simultaneously evaluated for comparison.<h4>Results</h4>BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific <i>in vitro</i> and <i>in vivo</i> when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [¹⁷⁷Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities K_D1 = 3.8 nM and K_D2 = 25 nM. The half-maximal inhibitory concentration for ^natLu-BQ7876 was 59 nM that is equal to 61 nM for ^natLu-PSMA-617. Cellular processing of [¹⁷⁷Lu]Lu-BQ7876 was accompanied by slow internalization. [¹⁷⁷Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3%ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen.<h4>Discussion</h4>Biodistribution studies in mice demonstrated that targeting properties of [¹⁷⁷Lu]Lu-BQ7876 are not inferior to properties of [¹⁷⁷Lu]Lu-PSMA-617, but do not offer any decisive advantages.2023-01-01T00:00:00Z20232025-04-18T16:44:40.13Z2025-04-07T04:10:22.881ZS-EPMC105656633782934510.3389/fonc.2023.1221103