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European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

01.06.2008 | Original article

⁶⁸Ga-labeled multimeric RGD peptides for microPET imaging of integrin α_vβ₃ expression

verfasst von: Zi-Bo Li, Kai Chen, Xiaoyuan Chen

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 6/2008

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Abstract

Purpose

We and others have reported that ¹⁸F- and ⁶⁴Cu-labeled arginine–glycine–aspartate (RGD) peptides allow positron emission tomography (PET) quantification of integrin α_vβ₃ expression in vivo. However, clinical translation of these radiotracers is partially hindered by the necessity of cyclotron facility to produce the PET isotopes. Generator-based PET isotope ⁶⁸Ga, with a half-life of 68 min and 89% positron emission, deserves special attention because of its independence of an onsite cyclotron. The goal of this study was to investigate the feasibility of ⁶⁸Ga-labeled RGD peptides for tumor imaging.

Methods

Three cyclic RGD peptides, c(RGDyK) (RGD1), E[c(RGDyK)]₂ (RGD2), and E{E[c(RGDyK)]₂}₂ (RGD4), were conjugated with macrocyclic chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and labeled with ⁶⁸Ga. Integrin affinity and specificity of the peptide conjugates were assessed by cell-based receptor binding assay, and the tumor targeting efficacy of ⁶⁸Ga-labeled RGD peptides was evaluated in a subcutaneous U87MG glioblastoma xenograft model.

Results

U87MG cell-based receptor binding assay using ¹²⁵I-echistatin as radioligand showed that integrin affinity followed the order of NOTA–RGD4 > NOTA–RGD2 > NOTA–RGD1. All three NOTA conjugates allowed nearly quantitative ⁶⁸Ga-labeling within 10 min (12–17 MBq/nmol). Quantitative microPET imaging studies showed that ⁶⁸Ga-NOTA–RGD4 had the highest tumor uptake but also prominent activity accumulation in the kidneys. ⁶⁸Ga-NOTA–RGD2 had higher tumor uptake (e.g., 2.8 ± 0.1%ID/g at 1 h postinjection) and similar pharmacokinetics (4.4 ± 0.4 tumor/muscle ratio, 2.0 ± 0.1 tumor/liver ratio, and 1.1 ± 0.1 tumor/kidney ratio) compared with ⁶⁸Ga-NOTA–RGD1.

Conclusions

The dimeric RGD peptide tracer ⁶⁸Ga-NOTA–RGD2 with good tumor uptake and favorable pharmacokinetics warrants further investigation for potential clinical translation to image integrin α_vβ₃.

Albelda SM, Mette SA, Elder DE, Stewart R, Damjanovich L, Herlyn M, et al. Integrin distribution in malignant melanoma: association of the β₃ subunit with tumor progression. Cancer Res. 1990;50:6757–64.PubMed

Bello L, Francolini M, Marthyn P, Zhang J, Carroll RS, Nikas DC, et al. α_vβ₃ and α_vβ₅ integrin expression in glioma periphery. Neurosurgery. 2001;49:380–9. discussion 90.PubMedCrossRef

Brooks PC, Stromblad S, Klemke R, Visscher D, Sarkar FH, Cheresh DA. Antiintegrin α_vβ₃ blocks human breast cancer growth and angiogenesis in human skin. J Clin Invest. 1995;96:1815–22.PubMedCrossRef

Puduvalli VK. Inhibition of angiogenesis as a therapeutic strategy against brain tumors. Cancer Treat Res. 2004;117:307–36.PubMed

Sengupta S, Chattopadhyay N, Mitra A, Ray S, Dasgupta S, Chatterjee A. Role of α_vβ₃ integrin receptors in breast tumor. J Exp Clin Cancer Res. 2001;20:585–90.PubMed

Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69:11–25.PubMedCrossRef

Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin α_vβ₃ for angiogenesis. Science. 1994;264:569–71.PubMedCrossRef

Friedlander M, Brooks PC, Shaffer RW, Kincaid CM, Varner JA, Cheresh DA. Definition of two angiogenic pathways by distinct α_v integrins. Science. 1995;270:1500–2.PubMedCrossRef

Horton MA. The α_vβ₃ integrin “vitronectin receptor”. Int J Biochem Cell Biol. 1997;29:721–5.PubMedCrossRef

10.

Jin H, Varner J. Integrins: roles in cancer development and as treatment targets. Br J Cancer. 2004;90:561–5.PubMedCrossRef

11.

Kumar CC. Integrin α_vβ₃ as a therapeutic target for blocking tumor-induced angiogenesis. Curr Drug Targets. 2003;4:123–31.PubMedCrossRef

12.

Jung KH, Lee KH, Paik JY, Ko BH, Bae JS, Lee BC, et al. Favorable biokinetic and tumor-targeting properties of ^99mTc-labeled glucosamino RGD and effect of paclitaxel therapy. J Nucl Med. 2006;47:2000–7.PubMed

13.

Zhang X, Xiong Z, Wu Y, Cai W, Tseng JR, Gambhir SS, et al. Quantitative PET imaging of tumor integrin α_vβ₃ expression with ¹⁸F-FRGD₂. J Nucl Med. 2006;47:113–21.PubMed

14.

Tucker GC. α_v integrin inhibitors and cancer therapy. Curr Opin Investig Drugs. 2003;4:722–31.PubMed

15.

Dijkgraaf I, Liu S, Kruijtzer JA, Soede AC, Oyen WJ, Liskamp RM, et al. Effects of linker variation on the in vitro and in vivo characteristics of an ¹¹¹In-labeled RGD peptide. Nucl Med Biol. 2007;34:29–35.PubMedCrossRef

16.

Dijkgraaf I, Kruijtzer JA, Liu S, Soede AC, Oyen WJ, Corstens FH, et al. Improved targeting of the α_vβ₃ integrin by multimerisation of RGD peptides. Eur J Nucl Med Mol Imaging. 2007;34:267–73.PubMedCrossRef

17.

Beer AJ, Haubner R, Goebel M, Luderschmidt S, Spilker ME, Wester HJ, et al. Biodistribution and pharmacokinetics of the. α_vβ₃-selective tracer ¹⁸F-galacto-RGD in cancer patients. J Nucl Med. 2005;46:1333–41.PubMed

18.

Liu S. Radiolabeled multimeric cyclic RGD peptides as integrin α_vβ₃ targeted radiotracers for tumor imaging. Mol Pharm. 2006;3:472–87.PubMedCrossRef

19.

Liu S, Edwards DS, Ziegler MC, Harris AR, Hemingway SJ, Barrett JA. ^99mTc-labeling of a hydrazinonicotinamide-conjugated vitronectin receptor antagonist useful for imaging tumors. Bioconjug Chem. 2001;12:624–9.PubMedCrossRef

20.

Sharma SD, Jiang J, Hadley ME, Bentley DL, Hruby VJ. Melanotropic peptide-conjugated beads for microscopic visualization and characterization of melanoma melanotropin receptors. Proc Natl Acad Sci USA. 1996;93:13715–20.PubMedCrossRef

21.

Mammen M, Chio S-K, Whitesides GM. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew Chem Int Ed Engl. 1998;37:2755–94.CrossRef

22.

Wu Y, Zhang X, Xiong Z, Cheng Z, Fisher DR, Liu S, et al. microPET imaging of glioma integrin α_vβ₃ expression using ⁶⁴Cu-labeled tetrameric RGD peptide. J Nucl Med. 2005;46:1707–18.PubMed

23.

Ye Y, Bloch S, Xu B, Achilefu S. Design, synthesis, and evaluation of near infrared fluorescent multimeric RGD peptides for targeting tumors. J Med Chem. 2006;49:2268–75.PubMedCrossRef

24.

Wu Z, Li Z, Cai W, He L, Chin F, Li F, et al. ¹⁸F-labeled mini-PEG spacered RGD dimer (¹⁸F-FPRGD2): synthesis and microPET imaging of α_vβ₃ integrin expression. Eur J Nucl Med Mol Imaging. 2007;34:1823–31.PubMedCrossRef

25.

Wu Z, Li ZB, Chen K, Cai W, He L, Chin FT, et al. microPET of Tumor Integrin α_vβ₃ Expression Using ¹⁸F-Labeled PEGylated Tetrameric RGD Peptide (¹⁸F-FPRGD4). J Nucl Med. 2007;48:1536–44.PubMedCrossRef

26.

Li ZB, Cai W, Cao Q, Chen K, Wu Z, He L, et al. ⁶⁴Cu-labeled tetrameric and octameric RGD peptides for small-animal PET of tumor α_vβ₃ integrin expression. J Nucl Med. 2007;48:1162–71.PubMedCrossRef

27.

Maecke HR, Hofmann M, Haberkorn U. ⁶⁸Ga-labeled peptides in tumor imaging. J Nucl Med. 2005;46(Suppl 1):172S–8S.PubMed

28.

Reubi JC, Schar JC, Waser B, Wenger S, Heppeler A, Schmitt JS, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27:273–82.PubMedCrossRef

29.

Haubner R, Wester HJ, Burkhart F, Senekowitsch-Schmidtke R, Weber W, Goodman SL, et al. Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics. J Nucl Med. 2001;42:326–36.PubMed

30.

Benedetti E, Morelli G, Accardo A, Mansi R, Tesauro D, Aloj L. Criteria for the design and biological characterization of radiolabeled peptide-based pharmaceuticals. BioDrugs. 2004;18:279–95.PubMedCrossRef

31.

Clarke ET, Martell AE. Stabilities of trivalent metal ion complexes of tetraacetate derivatives of 12-, 13- and 14-membered tetraazamacrocycles. Inorganica Chim Acta. 1991;190:37–46.CrossRef

32.

Clarke ET, Martell AE. Stabilities of the Fe(III), Ga(III), and In(III) chelates of N,N′,N′-triazacyclononanetriacetic acid. Inorganica Chim Acta. 1991;181:273–80.CrossRef

Titel: 68Ga-labeled multimeric RGD peptides for microPET imaging of integrin αvβ3 expression
verfasst von: Zi-Bo Li
Kai Chen
Xiaoyuan Chen
Publikationsdatum: 01.06.2008
Verlag: Springer-Verlag
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 6/2008
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-007-0692-y

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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