Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide

Ingrid Dijkgraaf; Samantha Y A Terry; William J McBride; David M Goldenberg; Peter Laverman; Gerben M Franssen; Wim J G Oyen; Otto C Boerman

doi:10.1002/cmmi.1523

Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide

Ingrid Dijkgraaf, Samantha Y A Terry, William J McBride, David M Goldenberg, Peter Laverman, Gerben M Franssen, Wim J G Oyen, Otto C Boerman

Imaging Chemistry & Biology

Research output: Contribution to journal › Article › peer-review

40 Citations (Scopus)

Abstract

Integrin αv β3 receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine-glycine-aspartatic acid (RGD) peptide and integrin αv β3 , but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of (18)F. In this study, the dimeric RGD peptide, E-[c(RGDfK)]2, was conjugated with NODAGA and radiolabeled with (18)F in a simple one-pot process with a radiolabeling yield of 20%, the whole process lasting only 45 min. NODAGA-E-[c(RGDfK)]2 labeled with (18)F at a specific activity of 1.8 MBq nmol(-1) and a radiochemical purity of 100% could be achieved. The logP value of (18)F-labeled NODAGA-E-[c(RGDfK)]2 was -4.26 ± 0.02. In biodistribution studies, (18)F-NODAGA-E-[c(RGDfK)]2 cleared rapidly from the blood with 0.03 ± 0.01 percentage injected dose per gram (%ID g(-1)) in the blood at 2 h p.i., mainly via the kidneys, and showed good in vivo stability. Tumor uptake of (18)F-NODAGA-E-[c(RGDfK)]2 (3.44 ± 0.20 %ID g(-1), 2 h p.i.) was significantly lower than that of reference compounds (68) Ga-labeled NODAGA-E-[c(RGDfK)]2 (6.26 ± 0.76 %ID g(-1) ; p <0.001) and (111) In-labeled NODAGA-E-[c(RGDfK)]2 (4.99 ± 0.64 %ID g(-1) ; p < 0.01). Co-injection of an excess of unlabeled NODAGA-E-[c(RGDfK)]2 along with (18)F-NODAGA-E-[c(RGDfK)]2 resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID g(-1)). The αv β3 integrin-expressing SK-RC-52 tumor could be successfully visualized by microPET with (18)F-labeled NODAGA-E-[c(RGDfK)]2 . In conclusion, NODAGA-E-[c(RGDfK)]2 could be labeled rapidly with (18)F using a direct aqueous, one-pot method and it accumulated specifically in αv β3 integrin-expressing SK-RC-52 tumors, allowing for visualization by microPET.

Original language	English
Pages (from-to)	238-45
Number of pages	8
Journal	Contrast Media & Molecular Imaging
Volume	8
Issue number	3
DOIs	https://doi.org/10.1002/cmmi.1523
Publication status	Published - 23 Apr 2013

Keywords

Animals
Dimerization
Female
Fluorine Radioisotopes
Gene Expression Regulation, Neoplastic
Integrin alphaVbeta3
Isotope Labeling
Metabolic Clearance Rate
Mice
Mice, Inbred C57BL
Mice, Nude
Molecular Imaging
Neoplasms, Experimental
Oligopeptides
Organ Specificity
Reproducibility of Results
Sensitivity and Specificity
Tissue Distribution
Tomography, Emission-Computed, Single-Photon

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/cmmi.1523

Cite this

@article{598a6bf00dd44cab86204175edea7fb1,

title = "Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide",

abstract = "Integrin αv β3 receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine-glycine-aspartatic acid (RGD) peptide and integrin αv β3 , but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of (18)F. In this study, the dimeric RGD peptide, E-[c(RGDfK)]2, was conjugated with NODAGA and radiolabeled with (18)F in a simple one-pot process with a radiolabeling yield of 20%, the whole process lasting only 45 min. NODAGA-E-[c(RGDfK)]2 labeled with (18)F at a specific activity of 1.8 MBq nmol(-1) and a radiochemical purity of 100% could be achieved. The logP value of (18)F-labeled NODAGA-E-[c(RGDfK)]2 was -4.26 ± 0.02. In biodistribution studies, (18)F-NODAGA-E-[c(RGDfK)]2 cleared rapidly from the blood with 0.03 ± 0.01 percentage injected dose per gram (%ID g(-1)) in the blood at 2 h p.i., mainly via the kidneys, and showed good in vivo stability. Tumor uptake of (18)F-NODAGA-E-[c(RGDfK)]2 (3.44 ± 0.20 %ID g(-1), 2 h p.i.) was significantly lower than that of reference compounds (68) Ga-labeled NODAGA-E-[c(RGDfK)]2 (6.26 ± 0.76 %ID g(-1) ; p <0.001) and (111) In-labeled NODAGA-E-[c(RGDfK)]2 (4.99 ± 0.64 %ID g(-1) ; p < 0.01). Co-injection of an excess of unlabeled NODAGA-E-[c(RGDfK)]2 along with (18)F-NODAGA-E-[c(RGDfK)]2 resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID g(-1)). The αv β3 integrin-expressing SK-RC-52 tumor could be successfully visualized by microPET with (18)F-labeled NODAGA-E-[c(RGDfK)]2 . In conclusion, NODAGA-E-[c(RGDfK)]2 could be labeled rapidly with (18)F using a direct aqueous, one-pot method and it accumulated specifically in αv β3 integrin-expressing SK-RC-52 tumors, allowing for visualization by microPET.",

keywords = "Animals, Dimerization, Female, Fluorine Radioisotopes, Gene Expression Regulation, Neoplastic, Integrin alphaVbeta3, Isotope Labeling, Metabolic Clearance Rate, Mice, Mice, Inbred C57BL, Mice, Nude, Molecular Imaging, Neoplasms, Experimental, Oligopeptides, Organ Specificity, Reproducibility of Results, Sensitivity and Specificity, Tissue Distribution, Tomography, Emission-Computed, Single-Photon",

author = "Ingrid Dijkgraaf and Terry, {Samantha Y A} and McBride, {William J} and Goldenberg, {David M} and Peter Laverman and Franssen, {Gerben M} and Oyen, {Wim J G} and Boerman, {Otto C}",

note = "Copyright {\textcopyright} 2013 John Wiley & Sons, Ltd.",

year = "2013",

month = apr,

day = "23",

doi = "10.1002/cmmi.1523",

language = "English",

volume = "8",

pages = "238--45",

journal = "Contrast Media & Molecular Imaging",

publisher = "Hindawi Limited",

number = "3",

}

TY - JOUR

T1 - Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide

AU - Dijkgraaf, Ingrid

AU - Terry, Samantha Y A

AU - McBride, William J

AU - Goldenberg, David M

AU - Laverman, Peter

AU - Franssen, Gerben M

AU - Oyen, Wim J G

AU - Boerman, Otto C

PY - 2013/4/23

Y1 - 2013/4/23

N2 - Integrin αv β3 receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine-glycine-aspartatic acid (RGD) peptide and integrin αv β3 , but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of (18)F. In this study, the dimeric RGD peptide, E-[c(RGDfK)]2, was conjugated with NODAGA and radiolabeled with (18)F in a simple one-pot process with a radiolabeling yield of 20%, the whole process lasting only 45 min. NODAGA-E-[c(RGDfK)]2 labeled with (18)F at a specific activity of 1.8 MBq nmol(-1) and a radiochemical purity of 100% could be achieved. The logP value of (18)F-labeled NODAGA-E-[c(RGDfK)]2 was -4.26 ± 0.02. In biodistribution studies, (18)F-NODAGA-E-[c(RGDfK)]2 cleared rapidly from the blood with 0.03 ± 0.01 percentage injected dose per gram (%ID g(-1)) in the blood at 2 h p.i., mainly via the kidneys, and showed good in vivo stability. Tumor uptake of (18)F-NODAGA-E-[c(RGDfK)]2 (3.44 ± 0.20 %ID g(-1), 2 h p.i.) was significantly lower than that of reference compounds (68) Ga-labeled NODAGA-E-[c(RGDfK)]2 (6.26 ± 0.76 %ID g(-1) ; p <0.001) and (111) In-labeled NODAGA-E-[c(RGDfK)]2 (4.99 ± 0.64 %ID g(-1) ; p < 0.01). Co-injection of an excess of unlabeled NODAGA-E-[c(RGDfK)]2 along with (18)F-NODAGA-E-[c(RGDfK)]2 resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID g(-1)). The αv β3 integrin-expressing SK-RC-52 tumor could be successfully visualized by microPET with (18)F-labeled NODAGA-E-[c(RGDfK)]2 . In conclusion, NODAGA-E-[c(RGDfK)]2 could be labeled rapidly with (18)F using a direct aqueous, one-pot method and it accumulated specifically in αv β3 integrin-expressing SK-RC-52 tumors, allowing for visualization by microPET.

AB - Integrin αv β3 receptors are expressed on activated endothelial cells during neovascularization to maintain tumor growth. Many radiolabeled probes utilize the tight and specific association between the arginine-glycine-aspartatic acid (RGD) peptide and integrin αv β3 , but one main obstacle for any clinical application of these probes is the laborious multistep radiosynthesis of (18)F. In this study, the dimeric RGD peptide, E-[c(RGDfK)]2, was conjugated with NODAGA and radiolabeled with (18)F in a simple one-pot process with a radiolabeling yield of 20%, the whole process lasting only 45 min. NODAGA-E-[c(RGDfK)]2 labeled with (18)F at a specific activity of 1.8 MBq nmol(-1) and a radiochemical purity of 100% could be achieved. The logP value of (18)F-labeled NODAGA-E-[c(RGDfK)]2 was -4.26 ± 0.02. In biodistribution studies, (18)F-NODAGA-E-[c(RGDfK)]2 cleared rapidly from the blood with 0.03 ± 0.01 percentage injected dose per gram (%ID g(-1)) in the blood at 2 h p.i., mainly via the kidneys, and showed good in vivo stability. Tumor uptake of (18)F-NODAGA-E-[c(RGDfK)]2 (3.44 ± 0.20 %ID g(-1), 2 h p.i.) was significantly lower than that of reference compounds (68) Ga-labeled NODAGA-E-[c(RGDfK)]2 (6.26 ± 0.76 %ID g(-1) ; p <0.001) and (111) In-labeled NODAGA-E-[c(RGDfK)]2 (4.99 ± 0.64 %ID g(-1) ; p < 0.01). Co-injection of an excess of unlabeled NODAGA-E-[c(RGDfK)]2 along with (18)F-NODAGA-E-[c(RGDfK)]2 resulted in significantly reduced radioactivity concentrations in the tumor (0.85 ± 0.13 %ID g(-1)). The αv β3 integrin-expressing SK-RC-52 tumor could be successfully visualized by microPET with (18)F-labeled NODAGA-E-[c(RGDfK)]2 . In conclusion, NODAGA-E-[c(RGDfK)]2 could be labeled rapidly with (18)F using a direct aqueous, one-pot method and it accumulated specifically in αv β3 integrin-expressing SK-RC-52 tumors, allowing for visualization by microPET.

KW - Animals

KW - Dimerization

KW - Female

KW - Fluorine Radioisotopes

KW - Gene Expression Regulation, Neoplastic

KW - Integrin alphaVbeta3

KW - Isotope Labeling

KW - Metabolic Clearance Rate

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Nude

KW - Molecular Imaging

KW - Neoplasms, Experimental

KW - Oligopeptides

KW - Organ Specificity

KW - Reproducibility of Results

KW - Sensitivity and Specificity

KW - Tissue Distribution

KW - Tomography, Emission-Computed, Single-Photon

U2 - 10.1002/cmmi.1523

DO - 10.1002/cmmi.1523

M3 - Article

C2 - 23606427

VL - 8

SP - 238

EP - 245

JO - Contrast Media & Molecular Imaging

JF - Contrast Media & Molecular Imaging

IS - 3

ER -

Imaging integrin alpha-v-beta-3 expression in tumors with an 18F-labeled dimeric RGD peptide

Abstract

Keywords

UN SDGs

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