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[ 177 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 [ 177 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 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, [ 177 Lu]Lu-SibuDAB showed increased binding to mouse and human plasma proteins (91 ± 1 and 88 ± 2%, respectively) compared to [ 177 Lu]Lu-RibuDAB (75 ± 2 and 79 ± 2%, respectively). In vivo , [ 177 Lu]Lu-SibuDAB was metabolically more stable than [ 177 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 [ 177 Lu]Lu-RibuDAB in mice was considerably faster [27% of injected activity (% IA), 1 h p.i.] than for [ 177 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 0→8d ) of the blood retention was determined for [ 177 Lu]Lu-SibuDAB as compared to [ 177 Lu]Lu-RibuDAB, whereas the kidney AUC 0→8d value of [ 177 Lu]Lu-SibuDAB was only half as high as for [ 177 Lu]Lu-RibuDAB. As a result, a more favorable tumor-to-kidney AUC 0→8d ratio was obtained for [ 177 Lu]Lu-SibuDAB, which was also visualized on SPECT/CT images. Based on its improved kidney clearance and higher metabolic stability, [ 177 Lu]Lu-SibuDAB was selected as the more favorable radioligand. Therapy studies performed with [ 177 Lu]Lu-SibuDAB (5 MBq/mouse) demonstrated the anticipated therapeutic superiority over the current gold-standard [ 177 Lu]Lu-PSMA-617 (5 MBq/mouse). The significantly increased survival time of mice treated with [ 177 Lu]Lu-SibuDAB as compared to those injected with [ 177 Lu]Lu-PSMA-617 justifies further development of this novel radioligand toward clinical application.

The strategy of using radioligands for targeting the prostate-specific membrane antigen (PSMA) revealed to be promising for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently developed albumin-binding PSMA radioligands showed a remarkably increased tumor uptake because of the enhanced blood circulation, but higher accumulation of activity was also observed in off-target organs and tissues. The aim of this study was to investigate the option of using fast-cleared, small-molecular-weight PSMA inhibitors (PSMA-11, 2-PMPA, and ZJ-43) to reduce the kidney uptake of [ 177 Lu]Lu-PSMA-ALB-56, a previously developed albumin-binding PSMA radioligand. Dual-isotope SPECT/CT imaging was performed with tumor-bearing mice coinjected with [ 177 Lu]Lu-PSMA-ALB-56 and a 2.5-fold molar excess of [ 67 Ga]Ga-PSMA-11. At early timepoints after injection, the high renal uptake of [ 67 Ga]Ga-PSMA-11 reduced the accumulation of [ 177 Lu]Lu-PSMA-ALB-56 in the kidneys substantially, whereas the tumor uptake of [ 177 Lu]Lu-PSMA-ALB-56 was only slightly affected. These findings were confirmed in biodistribution studies, which revealed reduced uptake of [ 177 Lu]Lu-PSMA-ALB-56 in the kidneys due to coadministered unlabeled PSMA-11 (9.1 ± 0.8% IA/g vs 46 ± 11% IA/g; 1 h p.i.). The tumor uptake of [ 177 Lu]Lu-PSMA-ALB-56 was almost the same at 1 h p.i., irrespective of whether or not PSMA-11 was coinjected (24 ± 6% IA/g vs 27 ± 7% IA/g). The application of [ 177 Lu]Lu-PSMA-ALB-56 with 2-PMPA or ZJ-43, respectively, showed similar results in biodistribution studies. Among all three tested PSMA inhibitors, 2-PMPA, applied at a 2.5-fold molar excess relative to [ 177 Lu]Lu-PSMA-ALB-56, was most effective to improve the tumor-to-kidney ratios over the first hours after injection of [ 177 Lu]Lu-PSMA-ALB-56. The concept of using a PSMA inhibitor together with [ 177 Lu]Lu-PSMA-ALB-56 appears promising in view of a clinical translation of this and possibly other long-circulating PSMA radioligands.

Recently, we developed an albumin-binding radioligand ( 177 Lu-PSMA-ALB-56), which showed higher PSMA-specific tumor uptake in mice than the previously developed 177 Lu-PSMA-617 under the same experimental conditions. Such a radioligand may be of interest also for PET imaging, possibly enabling better visualization of even small metastases at late time-points after injection. The aim of this study was, therefore, to modify PSMA-ALB-56 by exchanging the DOTA chelator with a NODAGA chelator for stable coordination of 64 Cu ( T 1/2 = 12.7 h; Eβ + av = 278 keV). The resulting NODAGA-functionalized PSMA-ALB-89 ligand, and the previously establish DOTA-functionalized PSMA-ALB-56 ligand were labeled with 64 Cu and evaluated in vitro and in vivo. Both radioligands showed plasma protein-binding properties in vitro and PSMA-specific uptake in PC-3 PIP cells. Biodistribution studies, performed in tumor-bearing mice, revealed high accumulation of 64 Cu-PSMA-ALB-89 in PSMA-positive PC-3 PIP tumor xenografts (25.9 ± 3.41% IA/g at 1 h p.i.), which was further increased at later time-points (65.1 ± 7.82% IA/g at 4 h p.i. and 97.1 ± 7.01% IA/g at 24 h p.i.). High uptake of 64 Cu-PSMA-ALB-89 was also seen in the kidneys, however, 64 Cu-PSMA-ALB-89 was efficiently excreted over time. Mice injected with 64 Cu-PSMA-ALB-56 showed increased accumulation of radioactivity in the liver (25.3 ± 4.20% IA/g) when compared to the liver uptake of 64 Cu-PSMA-ALB-89 (4.88 ± 0.21% IA/g, at 4 h p.i.). This was most probably due to in vivo instability of the 64 Cu-DOTA complex, which was also the reason for lower tumor uptake (49.7 ± 16.1% IA/g at 4 h p.i. and 28.3 ± 3.59% IA/g at 24 h p.i.). PET/CT imaging studies confirmed these findings and enabled excellent visualization of the PSMA-positive tumor xenografts in vivo after injection of 64 Cu-PSMA-ALB-89. These data indicate that 64 Cu-PSMA-ALB-89 is favorable over 64 Cu-PSMA-ALB-56 with regard to the in vivo stability and tissue distribution profile. Moreover, 64 Cu-PSMA-ALB-89 outperformed previously developed 64 Cu-labeled PSMA ligands. Further optimization of long-circulating PSMA-targeting PET radioligands will be necessary before translating this concept to the clinics.