PET imaging of integrins

All cells (excluding blood cells) adhere to the surrounding extracellular matrix (ECM) by membrane receptors, mainly integrins. Integrins are heterodimeric proteins, consisting of α and β subunits, which have a large extracellular domain, a single transmembrane domain, and short intracellular tail. The specificity of the integrin is determined by the combination of the α and β subunits. The cytoplasmic tail of integrins are connected to the cells cytoskeleton. Binding to and separation from their cytoplasmic signalling molecules, cytoskeleton, and ECM ligands are associated via conformational changes. Integrin receptors can signal bidirectionally: intracellular signalling pathways may activate or deactivate the extracellular part via large conformational changes.

ECM proteins expose short peptide loops, such as Arg-Gly-Asp (RGD) sequence, which are recognized by the integrins. RGD motif is found for example in fibronectin, vitronectin and fibrinogen. At least 24 integrins are known, and eight of them recognize RGD sequence (Steider et al., 2021). Endothelial cells express endoglin, which also contains the RGD motif.

Integrins are important in tissue remodelling, cell migration, proliferation, and differentiation. Haemostasis and regulation of blood clotting is largely based on integrins. Integrins mediate the entry of lymphocytes into inflamed tissue, and can therefore be targeted in therapy for autoimmune diseases. Integrins expressed by the cells of CNS are important in synaptic plasticity, synapse formation, and regulation of myelination and status of microglia.

Shank-associated RH domain-interacting protein (SHARPIN, alias SIPL1) is a cytosolic protein that controls integrin-dependent cell adhesion and migration in several normal and malignant cell types, and loss of SHARPIN correlates with increased integrin activity in mice (Siitonen et al., 2019).

Integrin αvβ3

Integrin αvβ3 is a cell membrane glycoprotein receptor ("vitronectin receptor") that interacts with specific ligands in extracellular matrix (ECM), playing a key role in angiogenesis, inflammation, fibrosis, osteoporosis, and tumour metastasis formation. Expression of αvβ3 integrin is increased in activated endothelial cells and tumour cells, but is low in most normal tissues.

Extracellular (interstitial) matrix proteins, such as vitronectin, fibronectin, and thrombospondin) contain a Arg-Gly-Asp (RGD) tripeptide sequence, which binds to many integrins, including αvβ3. Radiolabelled peptides containing the RGD peptide can be used to detect the increased expression of αvβ3 integrin in tumours, atherosclerosis, and infarcted myocardium. Multimerization of RGD-domains increases the affinity and specific uptake of the tracer (Dijkgraaf et al., 2011).

PET imaging of integrin αvβ3 is already an important tool for tumour diagnosis and treatment monitoring (Chen et al., 2016). [68Ga]-DOTA-E-[c(RGDfK)]2 is one of the proposed PET tracers for αvβ3 imaging.

Increased integrin αvβ3 expression is also a potential biomarker of successful tissue repair processes. After myocardial infarction, its expression is upregulated during angiogenesis. In rat model of myocardial infarction, increased uptake of [18F]galacto-RGD in the defect area predicted better healing (Sherif et al., 2012). Similar results have been obtained in patients with myocardial infarction using [18F]fluciclatide ([18F]AH111585) (Jenkins et al., 2017) and [18F]galacto-RGD (Makowski et al., 2021).

Imaging of integrin αvβ3 in the liver may be useful in detecting fibrosis in non-alcoholic steatohepatitis (Rokugawa et al., 2018).

Integrin αvβ5

Integrin αvβ5 has a role in regulation of the integrity of endothelial barrier; VEGF-induced vascular leakage is diminished when αvβ5 inactivated. Integrin αvβ5 is expressed on endothelial and epithelial cells, and fibroblasts. Blocking αvβ5 reduces ischemia-reperfusion damage in rat model of acute kidney injury (McCurley et al., 2017).

[68Ga]DOTA-RGD binds to both αvβ3 and αvβ5 integrins (Haukkala et al., 2009).

Integrin αvβ6

Epithelial integrin αvβ6 is expressed by many carcinoma cell types, providing a target for radionuclide therapy and imaging (Färber et al., 2018). Integrin αvβ6 activates transforming growth factor β (TGFβ, with isoforms 1-3), a growth-inhibiting cytokine. Carcinoma cells become insensitive to TGFβ-induced growth inhibition, and thus overexpression of αvβ6 helps tissue invasion as normal tissue growth is inhibited (Brown & Marshall, 2019).

Integrin αvβ6 is overexpressed in human pulmonary fibrosis, and its inhibition blocks pulmonary fibrosis without exacerbating inflammation (Horan et al., 2008; Decaris et al., 2021).

PET radioligands targeting αvβ6 have been developed (Hausner et al., 2009 and 2015; Singh et al., 2014; Notni et al., 2017), and used in humans for imaging carcinomas (Altmann et al., 2017; Roesch et al., 2018; Müller et al., 2019; Flechsig et al., 2019; Hausner et al., 2019) and idiopathic pulmonary fibrosis (Kimura et al., 2019; Lukey et al., 2020; Maher et al., 2020).

Integrin αvβ8

Integrin αvβ8 is an activator of TGFβ but by a different mechanism as αvβ6 (Mu et al., 2002). It is expressed in many human carcinomas (Takasaka et al., 2018). [68Ga]Triveoctin can be used for in vivo imaging of αvβ8 integrin (Quigley et al., 2020).

Integrin αIIbβ3

[18F]GP1 is a promising radioligand for αIIbβ3, and could be used for thrombus PET imaging (Lohrke et al., 2017; Chae et al., 2019).

Integrin α5β1

Integrin α5β1 is associated with activation of endothelial cells and angiogenesis. PET radioligands for integrin α5β1 imaging have been developed (D'Alessandria et al., 2016; Notni et al., 2016).

LFA-1 (CD11a/CD18)

Lymphocyte functions associated antigen 1 (LFA-1) is the heterodimer of integrins alpha L (CD11a) and beta 2 (CD18) chains. LFA-1 is found on lymphocytes, macrophages, and neutrophils, and it is involved in leukocyte trafficking from blood into the tissue, and binding to antigen presenting cells.

Mac-1 (CD11b/CD18)

Macrophage-1 antigen receptor (Mac-1) is the heterodimer of integrins alpha L (CD11b) and beta 2 (CD18) chains. Mac-1 is one of complement receptors, found on neutrophils, macrophages and NK cells, and it is involved in the innate immune system. Other complement receptors are formed with combination of CD18 and CD11c or CD11c.

See also:


Chen H, Niu G, Wu H, Chen X. Clinical application of radiolabeled RGD peptides for PET imaging of integrin αvβ3. Theranostics 2016; 6(1): 78-92. doi: 10.7150/thno.13242.

Dijkgraaf I, Yim CB, Franssen GM, Schuit RC, Luurtsema G, Liu S, Oyen WJ, Boerman OC. PET imaging of αvβ3 integrin expression in tumours with Ga-labelled mono-, di- and tetrameric RGD peptides. Eur J Nucl Med Mol Imaging 2011; 38(1): 128–137. doi: 10.1007/s00259-010-1615-x.

Grönman M, Tarkia M, Kiviniemi T, Halonen P, Kuivanen A, Savunen T, Tolvanen T, Teuho J, Käkelä M, Metsälä O, Pietilä M, Saukko P, Ylä-Herttuala S, Knuuti J, Roivainen A, Saraste A. Imaging of αvβ3 integrin expression in experimental myocardial ischemia with [68Ga]NODAGA-RGD positron emission tomography. J Transl Med. 2017; 15(1):144. doi: 10.1186/s12967-017-1245-1.

Lohrke J, Siebeneicher H, Berger M, Reinhardt M, Berndt M, Mueller A, Zerna M, Koglin N, Oden F, Bauser M, Friebe M, Dinkelborg LM, Huetter J, Stephens AW. 18F-GP1, a novel PET tracer designed for high-sensitivity, low-background detection of thrombi. J Nucl Med. 2017; 58(7): 1094-1099. doi: 10.2967/jnumed.116.188896.

Steiger K, Quigley NG, Groll T, Richter F, Zierke MA, Beer AJ, Weichert W, Schwaiger M, Kossatz S, Notni J. There is a world beyond αvβ3-integrin: multimeric ligands for imaging of the integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1 by positron emission tomography. EJNMMI Res. 2021; 11: 106. doi: 10.1186/s13550-021-00842-2.

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Updated at: 2022-01-03
Created at: 2017-03-05
Written by: Vesa Oikonen