Preclinical Investigations to Explore the Difference between the Diastereomers [177Lu]Lu-SibuDAB and [177Lu]Lu-RibuDAB toward Prostate Cancer Therapy

Abstract

[¹⁷⁷Lu]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 [¹⁷⁷Lu]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 in vitro and in vivo properties and to select the more favorable radioligand for further development. For this purpose, SibuDAB and RibuDAB containing (S)- and (R)-ibuprofen, respectively, were synthesized and labeled with lutetium-177. In vitro, the two isomers had similar properties; however, [¹⁷⁷Lu]Lu-SibuDAB showed increased binding to mouse and human plasma proteins (91 ± 1 and 88 ± 2%, respectively) compared to [¹⁷⁷Lu]Lu-RibuDAB (75 ± 2 and 79 ± 2%, respectively). In vivo, [¹⁷⁷Lu]Lu-SibuDAB was metabolically more stable than [¹⁷⁷Lu]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 [¹⁷⁷Lu]Lu-RibuDAB in mice was considerably faster [27% of injected activity (% IA), 1 h p.i.] than for [¹⁷⁷Lu]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_0→8d) of the blood retention was determined for [¹⁷⁷Lu]Lu-SibuDAB as compared to [¹⁷⁷Lu]Lu-RibuDAB, whereas the kidney AUC_0→8d value of [¹⁷⁷Lu]Lu-SibuDAB was only half as high as for [¹⁷⁷Lu]Lu-RibuDAB. As a result, a more favorable tumor-to-kidney AUC_0→8d ratio was obtained for [¹⁷⁷Lu]Lu-SibuDAB, which was also visualized on SPECT/CT images. Based on its improved kidney clearance and higher metabolic stability, [¹⁷⁷Lu]Lu-SibuDAB was selected as the more favorable radioligand. Therapy studies performed with [¹⁷⁷Lu]Lu-SibuDAB (5 MBq/mouse) demonstrated the anticipated therapeutic superiority over the current gold-standard [¹⁷⁷Lu]Lu-PSMA-617 (5 MBq/mouse). The significantly increased survival time of mice treated with [¹⁷⁷Lu]Lu-SibuDAB as compared to those injected with [¹⁷⁷Lu]Lu-PSMA-617 justifies further development of this novel radioligand toward clinical application.

Keywords: PSMA radioligands; albumin binder; ibuprofen; lutetium-177; prostate cancer; stereochemistry.