LAUSR

Simple Summary Prostate cancer continues to be the most frequently diagnosed form of cancer and the leading cause of cancer-related deaths among men. For a successful treatment plan and outcome, an early diagnosis, correct staging, and monitoring of treatment response are crucial. To improve this, a radiotracer could be used to target the two most abundant proteins overexpressed in prostate cancer: prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR). To date, no such heterodimeric radiotracer is used in the clinic. In this study, we have preclinically characterized and evaluated a galium-68 labelled PSMA/GRPR-targeting radiotracer for PET imaging of prostate cancer. We hope that the findings from this study will be able to contribute to designing better heterodimeric ligands, promote clinical translation of a heterodimer, and serve as a step towards a first-in-human study. Abstract The development of radioligands targeting prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) has shown promising results for the imaging and therapy of prostate cancer. However, studies have shown that tumors and metastases can express such targets heterogeneously. To overcome this issue and to improve protein binding, radioligands with the ability to bind both PSMA and GRPR have been developed. Herein, we present the preclinical characterization of [68Ga]Ga-BQ7812; a PSMA/GRPR-targeting radioligand for the diagnostic PET imaging of prostate cancer. This study aimed to evaluate [68Ga]Ga-BQ7812 to promote the translation of such imaging probes into the clinic. [68Ga]Ga-BQ7812 demonstrated rapid and specific binding to both targets in a PSMA/GRPR-expressing PC3-pip cell line. Results from the biodistribution study in PC3-pip xenografted mice showed specific binding to both targets, with the highest activity uptake at 1 h pi in tumor (PSMA+/GRPR+, 10.4 ± 1.0% IA/g), kidneys (PSMA+, 45 ± 16% IA/g), and pancreas (GRPR+, 5.6 ± 0.7% IA/g). At 3h pi, increased tumour-to-organ ratios could be seen due to higher retention in the tumor compared with other PSMA or GRPR-expressing organs. These results, together with low toxicity and an acceptable estimated dosimetry profile (total effective dose = 0.0083 mSv/MBq), support the clinical translation of [68Ga]Ga-BQ7812 and represent a step towards its first clinical trial.