A comparative PET imaging study of 44g Sc- and 68 Ga-labeled bombesin antagonist BBN2 derivatives in breast and prostate cancer models

Radiolabeled peptides play a central role in nuclear medicine as radiotheranostics for targeted imaging and therapy of cancer. We have recently proposed the use of metabolically stabilized GRPR antagonist BBN2 for radiolabeling with F and Ga and subsequent PET imaging of GRPRs in prostate cancer. The present work studied the impact of Sc- and Ga-labeled DOTA complexes attached to GRPR antagonist BBN2 on the in vitro GRPR binding affinity, and their biodistribution and tumor uptake profiles in MCF7 breast and PC3 prostate cancer models. DOTA-Ava-BBN2 was radiolabeled with radiometals Ga and Sc. Gastrin-releasing peptide receptor (GRPR) affinities of peptides were assessed in PC3 prostate cancer cells. GRPR expression profiles were studied in human breast cancer tissue samples and MCF7 breast cancer cells. PET imaging of Ga- and Sc-labeled peptides was performed in MCF7 and PC3 xenografts as breast and prostate cancer models. Radiopeptides [ Ga]Ga-DOTA-Ava-BBN2 and [ Sc]Sc-DOTA-Ava BBN2 were prepared in radiochemical yields of 70-80% (decay-corrected), respectively. High binding affinities were found for both peptides (IC = 15 nM ( Ga) and 5 nM ( Sc)). Gene expression microarray analysis revealed high GRPR mRNA expression levels in estrogen receptor (ER)-positive breast cancer, which was further confirmed with Western blot and immunohistochemistry. However, PET imaging showed only low tumor uptake of both radiotracers in MCF7 xenografts ([ Ga]Ga-DOTA-BBN2 (SUV 0.27 ± 0.06); [ Sc]Sc-DOTA-BBN2 (SUV 0.20 ± 0.03)). In contrast, high tumor uptake and retention were found for both radiopeptides in PC3 tumors ([ Ga]Ga-DOTA-BBN2 (SUV 0.46 ± 0.07); [ Sc]Sc-DOTA-BBN2 (SUV 0.51 ± 0.11)). Comparison of Ga- and Sc-labeled DOTA-Ava-BBN2 peptides revealed slight but noticeable differences of the radiometal with an impact on the in vitro GRPR receptor binding properties in PC3 cells. No differences were found in their in vivo biodistribution profiles in MCF7 and PC3 xenografts. Radiopeptides [ Ga]Ga-DOTA-Ava-BBN2 and [ Sc]Sc-DOTA-Ava-BBN2 displayed comparable tumor uptake and retention profiles with rapid blood and renal clearance profiles in both tumor models. The favorable PET imaging performance of [ Sc]Sc-DOTA-Ava-BBN2 in prostate cancer should warrant the development of an [ Sc]Sc-DOTA-Ava-BBN2 analog for clinical translation which comes with a main γ-line of much lower energy and intensity compared to Sc.