Preclinical Investigations to Explore the Difference between the Diastereomers [Lu]Lu-SibuDAB and [Lu]Lu-RibuDAB toward Prostate Cancer Therapy.

[Lu]Lu-Ibu-DAB-PSMA, a radioligand modified with ibuprofen as the albumin binder, showed higher accumulation in PSMA-positive tumors of mice than the clinically used [Lu]Lu-PSMA-617 but lower retention in non-targeted tissues than previously developed albumin-binding PSMA radioligands. The aim of this study was to investigate whether the stereochemistry of the incorporated ibuprofen affects the radioligand's and properties and to select the more favorable radioligand for further development. For this purpose, SibuDAB and RibuDAB containing ()- and ()-ibuprofen, respectively, were synthesized and labeled with lutetium-177. , the two isomers had similar properties; however, [Lu]Lu-SibuDAB showed increased binding to mouse and human plasma proteins (91 ± 1 and 88 ± 2%, respectively) compared to [Lu]Lu-RibuDAB (75 ± 2 and 79 ± 2%, respectively). , [Lu]Lu-SibuDAB was metabolically more stable than [Lu]Lu-RibuDAB with ∼90 vs ∼67% intact radioligand detected in the blood at 4 h post injection (p.i.). In line with the lower albumin-binding affinity, the blood clearance of [Lu]Lu-RibuDAB in mice was considerably faster [27% of injected activity (% IA), 1 h p.i.] than for [Lu]Lu-SibuDAB (50% IA, 1 h p.i.). Time-dependent biodistribution studies performed in tumor-bearing athymic nude mice showed high PSMA-specific tumor uptake for both isomers. A twofold increased area under the curve (AUC) of the blood retention was determined for [Lu]Lu-SibuDAB as compared to [Lu]Lu-RibuDAB, whereas the kidney AUC value of [Lu]Lu-SibuDAB was only half as high as for [Lu]Lu-RibuDAB. As a result, a more favorable tumor-to-kidney AUC ratio was obtained for [Lu]Lu-SibuDAB, which was also visualized on SPECT/CT images. Based on its improved kidney clearance and higher metabolic stability, [Lu]Lu-SibuDAB was selected as the more favorable radioligand. Therapy studies performed with [Lu]Lu-SibuDAB (5 MBq/mouse) demonstrated the anticipated therapeutic superiority over the current gold-standard [Lu]Lu-PSMA-617 (5 MBq/mouse). The significantly increased survival time of mice treated with [Lu]Lu-SibuDAB as compared to those injected with [Lu]Lu-PSMA-617 justifies further development of this novel radioligand toward clinical application.