(177)Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry

INTRODUCTION: 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 in vivo 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 (177)Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy. METHODS: BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [(177)Lu]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 in vivo, target specificity and dosimetry. [(177)Lu]Lu-PSMA-617 was simultaneously evaluated for comparison. RESULTS: BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [(177)Lu]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 (nat)Lu-BQ7876 was 59 nM that is equal to 61 nM for (nat)Lu-PSMA-617. Cellular processing of [(177)Lu]Lu-BQ7876 was accompanied by slow internalization. [(177)Lu]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. DISCUSSION: Biodistribution studies in mice demonstrated that targeting properties of [(177)Lu]Lu-BQ7876 are not inferior to properties of [(177)Lu]Lu-PSMA-617, but do not offer any decisive advantages.