Summary                         

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, preclinical characterization of [68Ga]Ga-BQ7812; a PSMA/GRPR-targeting radioligand for the diagnostic PET imaging of prostate cancer is presented. 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.

Results from nanoScan® PET/CT

In vivo imaging were carried out using BALB/c nu/nu mice bearing PC3-pip xenografts. Whole body  PET imaging of PC3-pip xenografted mice using a nanoScan PET/MR3T camera (Mediso Medical Imaging System Ltd., Budapest, Hungary) was conducted by the injection of [68Ga]Ga-BQ7812 (100 pmol, 8 MBq) dissolved in a total volume of 100 µL 1% BSA. Immediately after the PET scan, a CT scan was performed using a nanoScan SPECT/CT camera (Mediso Medical Imaging System Ltd., Budapest, Hungary) with the same bed. In blocked group, mice were co-injected with non-labelled NOTA-PEG2-RM26 (5 nmol) and non-labelled PSMA-11 (5 nmol), in addition to the gallium-68 labelled heterodimer. Imaging of the non-blocked (n = 2) and the PSMA/GRPR-blocked (n = 2) groups was performed at 1 and 3 h pi. Reconstruction of the PET/CT scans was conducted using Nucline nanoScan 3.04.014.0000 software.

Results revealed:

• Mice in the PSMA-blocked group demonstrated a statistically significantly lower uptake of [⁶⁸Ga]Ga-BQ7812 in the tumour and kidneys compared with the non-blocked group. 

• The uptake of [⁶⁸Ga]Ga-BQ7812 in the GRPR-blocked group was statistically significantly lower in the tumour and the pancreas compared with the non-blocked group.

• The nanoScan PET/CT images confirmed the results from the ex vivo measurements of the biodistribution study. An elevated activity uptake could be visualised in the kidneys and the tumour at 1 and 3 h pi. Upon blocking of PSMA and GRPR, the tumour is no longer visualised and the kidneys are not as well defined.

Representative nanoScan PET/CT images of PC3-pip xenografted mice injected with [⁶⁸Ga]Ga-BQ7812 (100 pmol, 8 MBq). To the left: 1 h pi.; in the middle: 3 h pi.; to the right: PSMA and GRPR blocked at 1 h pi.

Taken together, from a toxicity, biodistribution, and radiation dosimetry point of view, [⁶⁸Ga]Ga-BQ7812 could be considered a promising candidate for PET-imaging of PSMA/GRPR-expression in the clinics.

Full article on mdpi.com