Comparative preclinical biodistribution, dosimetry and endoradiotherapy in mCRPC using 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T

Objectives: Radiohybrid prostate-specific membrane antigen (rhPSMA)-ligands are applicable as radiochemical twins for both diagnostic PET imaging and endoradiotherapy. Based on preliminary data as diagnostic ligand, the isomer rhPSMA-7.3 is a promising candidate for potential endoradiotherapy. The aim of this preclinical evaluation was to assess biodistribution, dosimetry and therapeutic efficacy of 19F/177Lu-rhPSMA-7.3 in comparison to the established therapeutic agent 177Lu-PSMA I&T (imaging & therapy). Methods: Biodistribution of 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T was performed in LNCaP tumor bearing SCID-mice after sacrifice at defined time points up to 7 days (n = 5). Organs and tumors were dissected, injected dose per gram (%ID/g) was determined and dosimetry calculations were performed using OLINDA/EXM1.0. The therapeutic efficacy of a single dose of 30 MBq 19F/177Lu-rhPSMA-7.3 (n = 7) was compared with 177Lu-PSMA I&T (n = 7) and control groups (n = 6-7) using C4-2 tumor bearing SCID-mice by evaluating tumor growth and survival over 6 weeks post treatment. Results: The biodistribution of 19F/177Lu-rhPSMA-7.3 revealed fast blood clearance (0.63 %ID/g at 1 h p.i.) and highest activity uptake in the spleen and kidneys, particularly in the first hour (33.25 %ID/g and 207.6 %ID/g, respectively at 1 h p.i.) indicating a renal excretion pathway. Compared with 177Lu-PSMA I&T, 19F/177Lu-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 19F/177Lu-rhPSMA-7.3 was substantially higher (e.g. 7.47 µGy/MBq vs. 1.96 µGy/MBq at 200 mm3) compared with 177Lu-PSMA I&T. In most organs absorbed doses were higher for 177Lu-PSMA I&T. A single dose of 19F/177Lu-rhPSMA-7.3 showed a significantly higher tumor size reduction compared with 177Lu-PSMA I&T at the end of the experiment (P = 0.0167). At pre-defined termination of the experiment at 6 weeks 7/7 and 3/7 mice were still alive in the 19F/177Lu-rhPSMA-7.3 and 177Lu-PSMA I&T groups compared to the control groups with 0/7 and 0/6 mice. Conclusion:19F/177Lu-rhPSMA-7.3 can be considered a suitable candidate for clinical translation due to similar clearance kinetics and radiation dose to healthy organs, but superior tumor uptake and retention compared with 177Lu-PSMA I&T. Preliminary treatment experiments showed a favorable anti-tumor response.