A Cu-64/Cu-67 Bombesin ligand as a theranostic for cancer

Background: The gastrin releasing peptide receptor (GRPR) is a promising target for imaging and targeted radionuclide therapy for a variety of cancers including glioma, breast cancer and prostate cancer. Positron-emitting copper-64 has attractive physical characteristics for imaging and provides a diagnostic partner for the therapeutic radionuclide copper-67. A sarcophagine-based macrobicyclic cage amine conjugated to a bombesin (BBN) analogue was prepared. The complex was radiolabelled with [⁶⁴Cu]Cu^II or [⁶⁷Cu]Cu^II and the tumor targeting and therapeutic efficacy was evaluated in a PC-3 xenograft prostate cancer mouse model. The dosimetry of the [⁶⁷Cu]Cu(SAR-BBN) complex was evaluated in healthy mice.

Methods: A sarcophagine ligand containing a PEG-linker and a GRPR antagonist (SAR-BBN) was radiolabelled with [⁶⁴Cu]Cu^II or [⁶⁷Cu]Cu^II at either room temperature or 40°C in <20 min to give complexes with high radiochemical purity, without the need for further purification. Small animal PET/CT images and organ biodistribution data of PC-3 tumor-bearing athymic mice were acquired at 1, 4, and 24 hr post-injection following intravenous administration of [⁶⁴Cu]Cu(SAR-BBN). Efficacy of repeat administrations of 24 MBq [⁶⁷Cu]Cu(SAR-BBN) over a 3 week period (to a total of 144 MBq) was determined in PC-3 tumor-bearing athymic nude mice. The dosimetry of [⁶⁷Cu]Cu(SAR-BBN) was evaluated in healthy mice.

Results: [⁶⁴Cu]Cu(SAR-BBN) displayed excellent tumour uptake and significant tumor retention at 24 hours post-injection Biodistribution studies showed rapid clearance through the kidneys, as well as hepatobiliary clearance. Uptake was also seen in the pancreas, an organ which expresses GRPR. Therapy with [⁶⁷Cu]Cu(SAR-BBN) in the PC-3 prostate cancer model showed that it was well tolerated with no toxicity observed as assessed by body weight changes. [⁶⁷Cu]Cu(SAR-BBN) significantly inhibited tumor growth, with a tumor growth inhibition of 93.5% on day 22, the last day all mice remained in the study. [⁶⁷Cu]Cu(SAR-BBN) significantly increase survival (p < 0.005)These data demonstrate the suitability of this novel agent for clinical assessment in the treatment of prostate cancer, as well as other cancers expressing GRPR. Conclusion: [^64/67Cu]Cu(SAR-BBN) has excellent tumor uptake and retention, which was reflected in the significant anti-tumor activity that was similar to a published Lu-177 based compound. This study warrants further investigation for this product as a theranostic agent for all cancers expressing GRPR.