Synthesis and radiopharmacological evaluation of a high-affinity and metabolically stabilized super(18)F-labeled bombesin analogue for molecular imaging of gastrin-releasing peptide receptor-expressing prostate cancer

Introduction: Bombesin (BBN) and BBN analogues have attracted much attention as high-affinity ligands for selective targeting of the gastrin-releasing peptide (GRP) receptor. GRP receptors are overexpressed in a variety of human cancers including prostate cancer. Radiolabeled BBN derivatives are pro...

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Published in:Nuclear medicine and biology 2013-11, Vol.40 (8), p.1025-1034
Main Authors: Richter, S, Wuest, M, Krieger, S S, Rogers, B E, Friebe, M, Bergmann, R, Wuest, F
Format: Article
Language:English
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Summary:Introduction: Bombesin (BBN) and BBN analogues have attracted much attention as high-affinity ligands for selective targeting of the gastrin-releasing peptide (GRP) receptor. GRP receptors are overexpressed in a variety of human cancers including prostate cancer. Radiolabeled BBN derivatives are promising diagnostic probes for molecular imaging of GRP receptor-expressing prostate cancer. This study describes the synthesis and radiopharmacological evaluation of various metabolically stabilized fluorobenzoylated bombesin analogues (BBN-1, BBN-2, BBN-3). Methods: Three fluorobenzoylated BBN analogues containing an aminovaleric (BBN-1, BBN-2), or an aminooctanoic acid linker (BBN-3) were tested in a competitive binding assay against super(125)I-[Tyr super(4)]-BBN for their binding potency to the GRP receptor. Intracellular calcium release in human prostate cancer cells (PC3) was measured to determine agonistic or antagonistic profiles of fluorobenzoylated BBN derivatives. Bombesin derivative BBN-2 displayed the highest inhibitory potency toward GRP receptor (IC sub(50) = 8.7 plus or minus 2.2 nM) and was subsequently selected for radiolabeling with fluorine-18 ( super(18)F) through acylation with N-succinimidyl-4-[ super(18)F]fluorobenzoate ([ super(18)F]SFB). The radiopharmacological profile of super(18)F-labeled bombesin [ super(18)F]BBN-2 was evaluated in PC3 tumor-bearing NMRI nude mice involving metabolic stability studies, biodistribution experiments and dynamic small-animal PET studies. Results: All fluorobenzoylated BBN derivatives displayed high inhibitory potency toward the GRP receptor (IC sub(50) = 8.7-16.7 nM), and all compounds exhibited antagonistic profiles as determined in an intracellular calcium release assay. The super(18)F-labeled BBN analogue [ super(18)F]BBN-2 was obtained in 30% decay-corrected radiochemical yield with high radiochemical purity >95% after semi-preparative HPLC purification. [ super(18)F]BBN-2 showed high metabolic stability in vivo with 65% of the radiolabeled peptide remaining intact after 60 min p.i. in mouse plasma. Biodistribution experiments and dynamic small-animal PET studies demonstrated high tumor uptake of [ super(18)F]BBN-2 in PC3 xenografts (2.75 plus or minus 1.82 %ID/g after 5 min and 2.45 plus or minus 1.25 %ID/g after 60 min p.i.). Specificity of radiotracer uptake in PC3 tumors was confirmed by blocking experiments. Conclusion: The present study demonstrates that super(18)F-labeled BBN analogue [ super(
ISSN:0969-8051