In Vitro and In Vivo Evaluation of a F-18-Labeled High Affinity NOTA Conjugated Bombesin Antagonist as a PET Ligand for GRPR-Targeted Tumor Imaging

• Expression of the gastrin-releasing peptide receptor (GRPR) in prostate cancer suggests that this receptor can be used as a potential molecular target to visualize and treat these tumors. We have previously investigated an antagonist analog of bombesin (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to 1,4,7-triazacyclononane-N,N',N ''-triacetic acid (NOTA) via a diethylene glycol (PEG(2)) spacer (NOTA-P2-RM26) labeled with Ga-68 and In-111. We found that this conjugate has favorable properties for in vivo imaging of GRPR-expression. The focus of this study was to develop a F-18-labelled PET agent to visualize GRPR. NOTA-P2-RM26 was labeled with F-18 using aluminum-fluoride chelation. Stability, in vitro binding specificity and cellular processing tests were performed. The inhibition efficiency (IC50) of the [F-nat]AlF-NOTA-P2-RM26 was compared to that of the Ga-nat-loaded peptide using I-125-Tyr(4)-BBN as the displacement radioligand. The pharmacokinetics and in vivo binding specificity of the compound were studied. NOTA-P2-RM26 was labeled with F-18 within 1 h (60-65% decay corrected radiochemical yield, 55 GBq/mu mol). The radiopeptide was stable in murine serum and showed high specific binding to PC-3 cells. [F-nat]AlF-NOTA-P2-RM26 showed a low nanomolar inhibition efficiency (IC50=4.4 +/- 0.8 nM). The internalization rate of the tracer was low. Less than 14% of the cell-bound radioactivity was internalized after 4 h. The biodistribution of [F-18]AlF-NOTA-P2-RM26 demonstrated rapid blood clearance, low liver uptake and low kidney retention. The tumor uptake at 3 h p. i. was 5.5 +/- 0.7 % ID/g, and the tumor-to-blood, -muscle and -bone ratios were 87 +/- 42, 159 +/- 47, 38 +/- 16, respectively. The uptake in tumors, pancreas and other GRPR-expressing organs was significantly reduced when excess amount of non-labeled peptide was co-injected. The low uptake in bone suggests a high in vivo stability of the Al-F bond. High contrast PET image was obtained 3 h p. i. The initial biological results suggest that [F-18]AlF-NOTA-P2-RM26 is a promising candidate for PET imaging of GRPR in vivo.

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