Top

EJNMMI Research

Published in:

Open Access 01-12-2011 | Original research

Mini-PEG spacering of VAP-1-targeting ⁶⁸Ga-DOTAVAP-P1 peptide improves PET imaging of inflammation

Authors: Anu Autio, Tiina Henttinen, Henri J Sipilä, Sirpa Jalkanen, Anne Roivainen

Published in: EJNMMI Research | Issue 1/2011

Abstract

Background

Vascular adhesion protein-1 (VAP-1) is an adhesion molecule that plays a key role in recruiting leucocytes into sites of inflammation. We have previously shown that ⁶⁸Gallium-labelled VAP-1-targeting peptide (⁶⁸Ga-DOTAVAP-P1) is a positron emission tomography (PET) imaging agent, capable of visualising inflammation in rats, but disadvantaged by its short metabolic half-life and rapid clearance. We hypothesised that prolonging the metabolic half-life of ⁶⁸Ga-DOTAVAP-P1 could further improve its imaging characteristics. In this study, we evaluated a new analogue of ⁶⁸Ga-DOTAVAP-P1 modified with a mini-polyethylene glycol (PEG) spacer (⁶⁸Ga-DOTAVAP-PEG-P1) for in vivo imaging of inflammation.

Methods

Whole-body distribution kinetics and visualisation of inflammation in a rat model by the peptides ⁶⁸Ga-DOTAVAP-P1 and ⁶⁸Ga-DOTAVAP-PEG-P1 were evaluated in vivo by dynamic PET imaging and ex vivo by measuring the radioactivity of excised tissues. In addition, plasma samples were analysed by radio-HPLC for the in vivo stability of the peptides.

Results

The peptide with the mini-PEG spacer showed slower renal excretion but similar liver uptake as the original peptide. At 60 min after injection, the standardised uptake value of the inflammation site was 0.33 ± 0.07 for ⁶⁸Ga-DOTAVAP-P1 and 0.53 ± 0.01 for ⁶⁸Ga-DOTAVAP-PEG-P1 by PET. In addition, inflammation-to-muscle ratios were 6.7 ± 1.3 and 7.3 ± 2.1 for ⁶⁸Ga-DOTAVAP-P1 and ⁶⁸Ga-DOTAVAP-PEG-P1, respectively. The proportion of unchanged peptide in circulation at 60 min after injection was significantly higher for ⁶⁸Ga-DOTAVAP-PEG-P1 (76%) than for ⁶⁸Ga-DOTAVAP-P1 (19%).

Conclusion

The eight-carbon mini-PEG spacer prolonged the metabolic half-life of the ⁶⁸Ga-DOTAVAP-P1 peptide, leading to higher target-to-background ratios and improved in vivo PET imaging of inflammation.

Available only for authorised users

Salmi M, Jalkanen S: A 90-kilodalton endothelial cell molecule mediating lymphocyte binding in humans. Science 1992, 257: 1407–1409. 10.1126/science.1529341PubMedCrossRef

Jaakkola K, Jalkanen S, Kaunismäki K, Vänttinen E, Saukko P, Alanen K, Kallajoki M, Voipio-Pulkki LM, Salmi M: Vascular adhesion protein-1, intercellular adhesion molecule-1 and P-selectin mediate leukocyte binding to ischemic heart in humans. J Am Coll Cardiol 2000, 36: 122–129. 10.1016/S0735-1097(00)00706-3PubMedCrossRef

Smith DJ, Salmi M, Bono P, Hellman J, Leu T, Jalkanen S: Cloning of vascular adhesion protein 1 reveals a novel multifunctional adhesion molecule. J Exp Med 1998, 188: 17–27. 10.1084/jem.188.1.17PubMedCentralPubMedCrossRef

Salmi M, Jalkanen S: VAP-1: an adhesin and an enzyme. Trends Immunol 2001, 22: 211–216. 10.1016/S1471-4906(01)01870-1PubMedCrossRef

Tohka S, Laukkanen M-L, Jalkanen S, Salmi M: Vascular adhesion protein 1 (VAP-1) functions as a molecular brake during granulocyte rolling and mediates recruitment in vivo. FASEB J 2001, 15: 373–382. 10.1096/fj.00-0240comPubMedCrossRef

Jalkanen S, Salmi M: VAP-1 and CD73, endothelial cell surface enzymes in leukocyte extravasation. Arterioscler Thromb Vasc Biol 2008, 28: 18–26. 10.1161/ATVBAHA.107.159905PubMedCrossRef

Yegutkin GG, Salminen T, Koskinen K, Kurtis C, McPherson MJ, Jalkanen S, Salmi M: A peptide inhibitor of vascular adhesion protein-1 (VAP-1) blocks leukocyte-endothelium interactions under shear stress. Eur J Immunol 2004, 34: 2276–2285. 10.1002/eji.200424932PubMedCrossRef

Lankinen P, Mäkinen TJ, Pöyhönen TA, Virsu P, Salomäki S, Hakanen AJ, Jalkanen S, Aro HT, Roivainen A: (68)Ga-DOTAVAP-P1 PET imaging capable of demonstrating the phase of inflammation in healing bones and the progress of infection in osteomyelitic bones. Eur J Nucl Med Mol Imaging 2008, 35: 352–364. 10.1007/s00259-007-0637-5PubMedCrossRef

Ujula T, Salomäki S, Virsu P, Lankinen P, Mäkinen TJ, Autio A, Yegutkin GG, Knuuti J, Jalkanen S, Roivainen A: Synthesis, 68Ga labeling and preliminary evaluation of DOTA peptide binding vascular adhesion protein-1: a potential PET imaging agent for diagnosing. osteomyelitis. Nucl Med Biol 2009, 36: 631–641. 10.1016/j.nucmedbio.2009.04.008PubMedCrossRef

10.

Autio A, Ujula T, Luoto P, Salomäki S, Jalkanen S, Roivainen A: PET imaging of inflammation and adenocarcinoma xenografts using vascular adhesion protein 1 targeting peptide (68)Ga-DOTAVAP-P1: comparison with (18)F-FDG. Eur J Nucl Med Mol Imaging 2010, 37: 1918–1925. 10.1007/s00259-010-1497-yPubMedCrossRef

11.

Harris JM, Chess RB: Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2002, 3: 214–221.

12.

Lalor PF, Edwards S, McNab G, Salmi M, Jalkanen S, Adams D: Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells. J Immunol 2002, 169: 983–992.PubMedCrossRef

13.

Ujula T, Salomäki S, Autio A, Luoto P, Tolvanen T, Lehikoinen P, Viljanen T, Sipilä H, Härkönen P, Roivainen A: 68Ga-chloride PET reveals human pancreatic adenocarcinoma xenografts in rats--comparison with FDG. Mol Imaging Biol 2010, 12: 259–268. 10.1007/s11307-009-0267-3PubMedCentralPubMedCrossRef

14.

Chen X, Hou Y, Tohme M, Park R, Khankaldyyan V, Gonzales-Gomez I, Bading JR, Laug WE, Conti PS: Pegylated Arg-Gly-Asp peptide: 64Cu labeling and PET imaging of brain tumor alphavbeta3-integrin expression. J Nucl Med 2004, 45: 1776–1783.PubMed

15.

Wen X, Wu Q, Ke S, Ellis L, Charnsangavej C, Delpassand AS, Wallace S, Li C: Conjugation with (111)In-DTPA-poly(ethylene glycol) improves imaging of anti-EGF receptor antibody C225. J Nucl Med 2001, 42: 1530–1537.PubMed

16.

DeNardo SJ, Liu R, Albrecht H, Natarajan A, Sutcliffe JL, Anderson C, Peng L, Ferdani R, Cherry SR, Lam KS: 111In-LLP2A-DOTA polyethylene glycol-targeting a4b1 integrin: comparative pharmacokinetics for imaging and therapy of lymphoid malignancies. J Nucl Med 2009, 50: 625–634. 10.2967/jnumed.108.056903PubMedCrossRef

17.

Wu Z, Li ZB, Cai W, He L, Chin FT, Li F, Chen X: ¹⁸ F-labeled mini-PEG spacered RGD dimer (¹⁸ F-FPRGD2): synthesis and microPET imaging of α _v β ₃ integrin expression. Eur J Nucl Med Mol Imaging 2007, 34: 1823–1831. 10.1007/s00259-007-0427-0PubMedCentralPubMedCrossRef

18.

Liu Z, Niu G, Shi J, Liu S, Wang F, Liu S, Chen X: ⁶⁸ Ga-labeled cyclic RGD dimers with Gly ₃ and PEG ₄ linkers: promising agents for tumor integrin α _v β ₃ PET imaging. Eur J Nucl Med Mol Imaging 2009, 36: 947–957. 10.1007/s00259-008-1045-1PubMedCrossRef

19.

Liu Z, Liu S, Wang F, Liu S, Chen X: Noninvasive imaging of tumor integrin expression using ¹⁸ F-labeled RGD dimer peptide with PEG ₄ linkers. Eur J Nucl Med Mol Imaging 2009, 36: 1296–1307. 10.1007/s00259-009-1112-2PubMedCrossRef

20.

Ke S, Wen X, Wu QP, Wallace S, Charnsangavej C, Stachowiak AM, Stephens CL, Abbruzzese JL, Podoloff DA, Li C: Imaging taxane-induced tumor apoptosis using PEGylated, ¹¹¹ In-labeled annexin V. J Nucl Med 2004, 45: 108–115.PubMed

21.

Burtea C, Laurent S, Lancelot E, Ballet S, Murariu O, Rousseaux O, Port M, Vander Elst L, Corot C, Muller RN: Peptidic targeting of phosphatidylserine for the MRI detection of apoptosis in atherosclerotic plaques. Mol Pharm 2009, 6: 1903–1919. 10.1021/mp900106mPubMedCrossRef

22.

Ke T, Jeong EK, Wang X, Feng Y, Parker DL, Lu ZR: RGD targeted poly(l-glutamic acid)-cystamine-(Gd-DO3A) conjugate for detecting angiogenesis biomarker α _v β ₃ integrin with MRT _I mapping. Int J Nanomedicine 2007, 2: 191–199.PubMedCentralPubMed

23.

Silvola J, Autio A, Luoto P, Jalkanen S, Roivainen A: Preliminary evaluation of novel 68Ga-DOTAVAP-PEG-P2 peptide targeting vascular adhesion protein-1. Clin Physiol Funct Imaging 2010, 30: 75–78. 10.1111/j.1475-097X.2009.00907.xPubMedCrossRef

Title: Mini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflammation
Authors: Anu Autio
Tiina Henttinen
Henri J Sipilä
Sirpa Jalkanen
Anne Roivainen
Publication date: 01-12-2011
Publisher: Springer Berlin Heidelberg
Published in: EJNMMI Research / Issue 1/2011
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/2191-219X-1-10

At a glance: The STEP trials

Springer Medicine

Mini-PEG spacering of VAP-1-targeting ⁶⁸Ga-DOTAVAP-P1 peptide improves PET imaging of inflammation

Abstract

Background

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2011

Reflections on the theory of "silver bullet" octreotide tracers: implications for ligand-receptor interactions in the age of peptides, heterodimers, receptor mosaics, truncated receptors, and multifractal analysis

Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors

Imaging technologies for preclinical models of bone and joint disorders

Experimental α-particle radioimmunotherapy of breast cancer using 227Th-labeled p-benzyl-DOTA-trastuzumab

Use of a beta microprobe system to measure arterial input function in PET via an arteriovenous shunt in rats

Diagnostic evaluation of three cardiac software packages using a consecutive group of patients