Related Experiment Video
Updated: Jan 14, 2026
09:44
Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction
Published on: January 29, 2019
10.5K
Optimizing uPAR-targeting radiopeptides for improved tissue distribution: progress towards radionuclide therapy.
Christian Vaccarin1, Darja Beyer1, Jerome V Schmid1
1Center for Radiopharmaceutical Sciences, PSI Center for Life Sciences, Villigen-PSI, 5232, Switzerland.
European Journal of Nuclear Medicine and Molecular Imaging
|October 27, 2025
Summary
New radiopeptides targeting urokinase-type plasminogen activator receptor (uPAR) were developed with enhanced albumin binding. [177Lu]Lu-uPAR-11 demonstrated superior tissue distribution and xenograft accumulation, making it a promising candidate for clinical translation.
Area of Science:
- Nuclear medicine
- Radiopharmaceutical chemistry
- Molecular imaging
Background:
- The urokinase-type plasminogen activator receptor (uPAR) is a promising target for cancer imaging and therapy.
- Improving the pharmacokinetic profiles of targeting agents is crucial for effective delivery to tumor sites.
- Albumin-binding moieties can enhance the circulation time and tissue distribution of radiopeptides.
Purpose of the Study:
- To develop novel radiopeptides targeting uPAR, incorporating an albumin-binding moiety to optimize tissue distribution.
- To synthesize and characterize a series of uPAR-targeting radiopeptides with varying linker and chelator designs.
- To evaluate the in vitro and in vivo performance of these novel radiopeptides compared to a non-albumin-binding control.
Main Methods:
- Synthesis of AE105 nonapeptide derivatives with p-tolyl-based albumin binders, variable linkers, and chelators.
- Radiolabeling with Lutetium-177 ([177Lu]).
- In vitro assessment of stability, albumin-binding affinity, and uPAR-binding affinity using HEK-uPAR cells.
- In vivo evaluation through biodistribution and SPECT/CT imaging in HEK-uPAR xenografted nude mice.
Main Results:
- Radiopeptides exhibited 11-155-fold higher albumin-binding affinity compared to [177Lu]Lu-DOTA-AE105.
- uPAR-binding affinity was comparable to the control, with KD values in the range of 31–42 nM.
- Xenograft accumulation was significantly higher (7-18 fold) for the novel radiopeptides (6.0-16% IA/g at 4 h p.i.).
- PEG linkers enhanced xenograft accumulation, while alkane linkers resulted in high blood retention.
- DOTAGA chelator led to unfavorable kidney retention.
Conclusions:
- [177Lu]Lu-uPAR-11, featuring PEG spacers, demonstrated the most favorable profile for clinical translation.
- This radiopeptide exhibited enhanced uPAR targeting and improved tissue distribution.
- Future research will investigate the therapeutic potential of [177Lu]Lu-uPAR-11 in preclinical tumor models.
