Rerouting the metabolic pathway of (18)F-labeled peptides: the influence of prosthetic groups

Current translational cancer research is directed to the development of high affinity peptide ligands for targeting neuropeptide receptors overexpressed in different types of cancer. Besides their desired high binding affinity to the receptor, the suitability of radiolabeled peptides as targeting ve...

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Bibliographic Details
Published in:Bioconjugate chemistry 2015-02, Vol.26 (2), p.201-212
Main Authors: Richter, Susan, Wuest, Melinda, Bergman, Cody N, Way, Jenilee D, Krieger, Stephanie, Rogers, Buck E, Wuest, Frank
Format: Article
Language:English
Subjects:
Animals
Bombesin - analogs & derivatives
Bombesin - metabolism
Bombesin - pharmacokinetics
Cell Line, Tumor
Fluorodeoxyglucose F18 - analogs & derivatives
Fluorodeoxyglucose F18 - metabolism
Fluorodeoxyglucose F18 - pharmacokinetics
Humans
Male
Mice
Mice, Inbred BALB C
Positron-Emission Tomography - methods
Prostate - pathology
Prostatic Neoplasms - diagnosis
Prostatic Neoplasms - pathology
Tissue Distribution
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Summary:Current translational cancer research is directed to the development of high affinity peptide ligands for targeting neuropeptide receptors overexpressed in different types of cancer. Besides their desired high binding affinity to the receptor, the suitability of radiolabeled peptides as targeting vectors for molecular imaging and therapy depends on additional aspects such as high tumor-to-background ratio, favorable clearance pattern from nontarget tissue, and sufficient metabolic stability in vivo. This study reports how a switch from the prosthetic group, N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]SFB), to 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F]FDG) effects the metabolic pathway of an (18)F-labeled bombesin derivative, QWAV-Sar-H-FA01010-Tle-NH2. (18)F-Labeled bombesin derivatives represent potent peptide ligands for selective targeting of gastrin-releasing peptide (GRP) receptor-expressing prostate cancer. Radiosynthesis of (18)F-labeled bombesin analogues [(18)F]FBz-Ava-BBN2 and [(18)F]FDG-AOAc-BBN2 was achieved in good radiochemical yields of ~50% at a specific activity exceeding 40 GBq/μmol. Both nonradioactive compounds FBz-Ava-BBN2 and FDG-AOAc-BBN2 inhibited binding of [(125)I]Tyr(4)-bombesin(1-14) in PC3 cells with IC50 values of 9 and 16 nM, respectively, indicating high inhibitory potency. Influence of each prosthetic group was further investigated in PC3 mouse xenografts using dynamic small animal PET imaging. In comparison to [(18)F]FBz-Ava-BBN2, total tumor uptake levels were doubled after injection of [(18)F]FDG-AOAc-BBN2 while renal elimination was increased. Blood clearance and in vivo metabolic stability were similar for both compounds. The switch from [(18)F]SFB to [(18)F]FDG as the prosthetic group led to a significant reduction in lipophilicity which resulted in more favorable renal clearance and increased tumor uptake. The presented single step radiolabeling-glycosylation approach represents an innovative strategy for site-directed peptide labeling with the short-lived positron emitter (18)F while providing a favorable pharmacokinetic profile of (18)F-labeled peptides.
ISSN:1520-4812
DOI:10.1021/bc500599m