In Vitro and in Vivo Characterization of Novel ¹⁸F-Labeled Bombesin Analogues for Targeting GRPR-Positive Tumors

Abstract

The gastrin-releasing peptide receptor (GRPR) is overexpressed on a number of human tumors and has been targeted with radiolabeled bombesin analogues for the diagnosis and therapy of these cancers. Seven bombesin analogues containing various linkers and peptide sequences were designed, synthesized, radiolabeled with (18)F, and characterized in vitro and in vivo as potential PET imaging agents. Binding studies displayed nanomolar binding affinities toward human GRPR for all synthesized bombesin analogues. Two high-affinity peptide candidates 6b (K(i) = 0.7 nM) and 7b (K(i) = 0.1 nM) were chosen for further in vivo evaluation. Both tracers revealed specific uptake in GRPR-expressing PC-3 tumors and the pancreas. Compared to [(18)F]6b, compound [(18)F]7b was characterized by superior tumor uptake, higher specificity of tracer uptake, and more favorable tumor-to-nontarget ratios. In vivo PET imaging allowed for the visualization of PC-3 tumor in nude mice suggesting that [(18)F]7b is a promising PET tracer candidate for the diagnosis of GRPR-positive tumors in humans.

A High-Affinity, High-Stability Photoacoustic Agent for Imaging Gastrin-Releasing Peptide Receptor in Prostate Cancer

“…indicated hepatobilliary excretion as gallbladder, liver and intestine displayed the highest photoacoustic signal. Similar clearance route was observed for some of the other GRPR antagonist agents (18, 26, 38). …”

“…As the lifetime greatly depends on the size of the agent, we will explore pegylation as a means to increase the size and improve pharmacokinetics of the agent. In addition, as linkers seem to play an important role for tumor targeting we will investigate amino acids with different size and charge to optimize the targeting efficiency of the agent (18). Lastly, it will be important to determine the targeting ability of the agent in other prostate tumor models such as orthotropic, androgen dependent and independent.…”

Bombesin related peptides/receptors and their promising therapeutic roles in cancer imaging, targeting and treatment

“…A number of recent studies using various radiolabeled( 188 Re, 55/57 Co, 111 In, 64 Cu, 99M Tc, 68 Ga, 18 F) BnR-agonists(primarily-GRPR-agonists) show imaging[16•,73,74,100,121,145,146,147•,148–155] or targeted-tumoral delivery of cytotoxic-radioisotopes( 177 Lu, 188 Re, 111 In, 64 Cu, 18 F)[16,74,77,100,147•,154] to prostate-cancer-cells both in vitro [16,73,74,81,121,145–147•,149,152–155] and in vivo to image prostate-cancer xenografts in nude-mice[16•,73,74,77,81,100,121,145,146,147•,148,149,151–155]. In two comparative studies in vivo of xenografts of the prostate-cancer-cell-line[155,156], PC-3, in nude-mice, a 68 Ga-labeled-BnR-agonist or 18 F-labeled-Bn-antagonist(BAY 86-4367) showed greater tumor-uptake with lower background than a metabolic probe, which is increasingly used in prostate-cancer patients.…”

GPCRs and cancer

“…In this regard, it was demonstrated that the anti-tumor activity of GrP antagonists involves different mechanisms as the reduction of EGFR and Her2 levels, the alteration of MAPK, PKC, pAkt, and COX-2 signaling, the attenuation of c-fos and c-jun expression, the modulation of wild-type and mutated forms of p53 along with an alteration of Bcl-2/BAX ratio, the inhibition of vascular endothelial growth factor (VEGF) [47] . Radiolabeled GrP analogues represent another chance in targeting GrP receptors, thus they are currently considered promising radiopharmaceuticals for detection and treatment of different types of tumors [48,49] .…”