Efficient (18)F-labeling of large 37-amino-acid pHLIP peptide analogues and their biological evaluation Journal Article
| Authors: | Daumar, P.; Wanger-Baumann, C. A.; Pillarsetty, N.; Fabrizio, L.; Carlin, S. D.; Andreev, O. A.; Reshetnyak, Y. K.; Lewis, J. S. |
| Article Title: | Efficient (18)F-labeling of large 37-amino-acid pHLIP peptide analogues and their biological evaluation |
| Abstract: | Solid tumors often develop an acidic microenvironment, which plays a critical role in tumor progression and is associated with increased level of invasion and metastasis. The 37-residue pH (low) insertion peptide (pHLIP) is under study as an imaging platform because of its unique ability to insert into cell membranes at a low extracellular pH (pH e < 7). Labeling of peptides with [ 18F]-fluorine is usually performed via prosthetic groups using chemoselective coupling reactions. One of the most successful procedures involves the alkyne-azide copper(I) catalyzed cycloaddition (CuAAC). However, none of the known "click" methods have been applied to peptides as large as pHLIP. We designed a novel prosthetic group and extended the use of the CuAAC "click chemistry" for the simple and efficient 18F-labeling of large peptides. For the evaluation of this labeling approach, a d-amino acid analogue of WT-pHLIP and an l-amino acid control peptide K-pHLIP, both functionalized at the N-terminus with 6-azidohexanoic acid, were used. The novel 6-[ 18F]fluoro-2-ethynylpyridine prosthetic group, was obtained via nucleophilic substitution on the corresponding bromo-precursor after 10 min at 130 °C with a radiochemical yield of 27.5 ± 6.6% (decay corrected) with high radiochemical purity ≥98%. The subsequent Cu I-catalyzed "click" reaction with the azido functionalized pHLIP peptides was quantitative within 5 min at 70 °C in a mixture of water and ethanol using Cu-acetate and sodium l-ascorbate. [ 18F]-d-WT-pHLIP and [ 18F]-l-K-pHLIP were obtained with total radiochemical yields of 5-20% after HPLC purification. The total reaction time was 85 min including formulation. In vitro stability tests revealed high stability of the [ 18F]-d-WT-pHLIP in human and mouse plasma after 120 min, with the parent tracer remaining intact at 65% and 85%, respectively. PET imaging and biodistribution studies in LNCaP and PC-3 xenografted mice with the [ 18F]-d-WT-pHLIP and the negative control [ 18F]-l-K-pHLIP revealed pH-dependent tumor retention. This reliable and efficient protocol promises to be useful for the 18F-labeling of large peptides such as pHLIP and will accelerate the evaluation of numerous [ 18F]-pHLIP analogues as potential PET tracers. © 2012 American Chemical Society. |
| Journal Title: | Bioconjugate Chemistry |
| Volume: | 23 |
| Issue: | 8 |
| ISSN: | 1043-1802 |
| Publisher: | American Chemical Society |
| Date Published: | 2012-08-15 |
| Start Page: | 1557 |
| End Page: | 1566 |
| Language: | English |
| DOI: | 10.1021/bc3000222 |
| PROVIDER: | scopus |
| PUBMED: | 22784215 |
| PMCID: | PMC3529145 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 September 2012" - "CODEN: BCCHE" - "Source: Scopus" |
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134Pillarsetty -
4Daumar -
461Lewis -
83Carlin -
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Fabrizio
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