Comparative Preclinical Biodistribution, Dosimetry, and Endoradiotherapy in Metastatic Castration-Resistant Prostate Cancer Using F/Lu-rhPSMA-7.3 and Lu-PSMA I&T.

Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands are applicable as radiochemical twins for both diagnostic PET imaging and endoradiotherapy. On the basis of preliminary data as a diagnostic ligand, the isomer rhPSMA-7.3 is a promising candidate for potential endoradiotherapy. The aim of this preclinical evaluation was to assess the biodistribution, dosimetry, and therapeutic efficacy of F/Lu-rhPSMA-7.3 in comparison to the established therapeutic agent Lu-PSMA I&T (imaging and therapy). The biodistribution of F/Lu-rhPSMA-7.3 and Lu-PSMA I&T was determined in LNCaP tumor-bearing severe combined immunodeficiency (SCID) mice after sacrifice at defined time points up to 7 d ( = 5). Organs and tumors were dissected, percentage injected dose per gram (%ID/g) was determined, and dosimetry was calculated using OLINDA/EXM, version 1.0. The therapeutic efficacy of a single 30-MBq dose of F/Lu-rhPSMA-7.3 ( = 7) was compared with that of Lu-PSMA I&T in treatment groups ( = 7) and control groups ( = 6-7) using C4-2 tumor-bearing SCID mice by evaluating tumor growth and survival over 6 wk after treatment. The biodistribution of F/Lu-rhPSMA-7.3 revealed fast blood clearance (0.63 %ID/g at 1 h after injection), and the highest activity uptake was in the spleen and kidneys, particularly in the first hour (33.25 %ID/g and 207.6 %ID/g, respectively, at 1 h after injection), indicating a renal excretion pathway. Compared with Lu-PSMA I&T, F/Lu-rhPSMA-7.3 exhibited an initial (1 h) 2.6-fold higher tumor uptake in LNCaP xenografts and a longer retention (4.5 %ID/g vs. 0.9 %ID/g at 168 h). The tumor dose of F/Lu-rhPSMA-7.3 was substantially higher (e.g., 7.47 vs. 1.96 µGy/MBq at 200 mm) than that of Lu-PSMA I&T. In most organs, absorbed doses were higher for Lu-PSMA I&T. A significantly greater tumor size reduction was shown for a single dose of F/Lu-rhPSMA-7.3 than for Lu-PSMA I&T at the end of the experiment ( = 0.0167). At the predefined termination of the experiment at 6 wk, 7 of 7 and 3 of 7 mice were still alive in the F/Lu-rhPSMA-7.3 and Lu-PSMA I&T groups, respectively, compared with the respective control groups, with 0 of 7 and 0 of 6 mice. Compared with Lu-PSMA I&T, F/Lu-rhPSMA-7.3 can be considered a suitable candidate for clinical translation because it has similar clearance kinetics and a similar radiation dose to healthy organs but superior tumor uptake and retention. Preliminary treatment experiments showed a favorable antitumor response.