Introduction: Bombesin (BBN) has become focus of interest, as its BB2 receptors are known to be overexpressed in prostate, breast, colon, pancreatic and lung tumor, as long as glioblastomas and neuroblastomas. BBN agonists and antagonists have already been radiolabeled for those tumors diagnosing and treatment by nuclear medicine techniques and promising results were obtained in preclinical and clinical studies. However, most of them exhibited high abdominal accumulation, especially in pancreas and intestines, which can compromise diagnosis accuracy and cause serious adverse effects in therapy.

Objective: The goal of the present work was to evaluate the potential new a BBN derivative labeled with ¹¹¹In for BB2 positive tumors diagnosis by single photon emission tomography (SPECT).

Materials and methods: The structure of the studied peptide was DOTA-Tyr-Glyn-BBN(6-13)-Nle (BEYG5N), where DOTA is the chelator, n is the number of glycine aminoacids in the spacer and BBN(6-13) is the original bombesin sequence from the aminoacid 6 to 13. The BBN derivative was evaluated in in vitro and in vivo studies in different BB2 expressing prostate (LNCaP and PC-3) and breast (T-47D) tumor cell lines. In vitro studies included saturation binding, internalization and efflux assays. In vivo stability in plasma was performed in BALB/c mice 5 and 15 minutes p.i. and biodistribution, microSPECT/CT imaging and ex-vivo stability in tissues were performed in SCID mice bearing PC-3 or LNCaP prostate tumor xenografts.

Results The peptide was radiolabeled with ¹¹¹In at high radiochemical purity (> 95 %) and high specific activity (100 GBq/μmol). Saturation binding assays on prostate (PC-3 e LNCaP) and breast (T-47D) tumor cells showed higher binding (higher Bmax) to PC-3 cells and similar affinity (Kd) for PC-3 and LNCaP cells, but the affinity was lower for T-47D cells. ¹¹¹In-BEYG5N was also more internalized by PC-3 cells. In vivo studies showed ¹¹¹In-BEYG5N present low stability in mice serum, but this low stability did not avoid the uptake of the peptide by PC-3 and LNCaP tumor in vivo. Although this last tumor has shown 2-fold less BB2 receptors than PC-3 tumor, LNCaP and PC-3 tumor uptake was similar (1 % of total injected activity per gram of tumor). In addition, the radiopeptide presented high stability in PC-3 tumor. Finally, nanoSPECT/CT imaging of PC-3 and LNCaP was possible with the radiopeptide and both tumors could be clearly identified with the advantage of lower abdominal accumulation when compared to published derivatives.

Conclusion: ¹¹¹In-BEYG5N is a promising tool for BB2 expressing tumors diagnosis by SPECT. Clinical studies should be performed in order to evaluate the value of this new radiopharmaceutical for tumor diagnosing in humans.

Instituição: Directory of Radiopharmacy (DIRF), Nuclear and Energy Research Institute (IPEN)