Peptides in PET imaging
Radiolabelled peptides, as well as antibodies and oligonucleotides, can be highly specific to their target (affibodies), and are relatively small, with fast clearance. Most of the currently used peptides are modifications from naturally occurring peptides, but the developments in molecular modelling allow development of novel peptides for any target. Peptides that consist of up to 50 amino acids have sufficiently small size to be able to diffuse into tumour tissue, and do not usually activate the immune system to produce antibodies.
Peptides are commonly labelled with bifunctional chelators (for example DOTA and NOTA) and metal isotopes: while labelling with 18F and 11C is possible, the chelators offer the possibility to switch the positron emitting radiometal, usually 68Ga or 64Cu, to a radiotherapeutic nuclide, such as 90Y or 177Lu.
Several radiolabelled peptides have been developed targeting for example neuropeptide receptors, prostate-specific membrane antigen (PSMA), integrins, GLP-1 receptor, HER2 (Tolmachev et al., 2018), and chemokine receptors. For cancer imaging, peptides that bind to two receptors could increase the sensitivity, since some tumours may not overexpress a certain target; for example, [68Ga]NOTARGD-BBN binds to both integrin αvβ3 and bombesin receptors (Liu et al., 2009), and DUPA-6-Ahx-([64Cu]NODAGA)-5-Ava-BBN(7-14)NH2 binds to bombesin receptors and PSMA (Bandari et al., 2014).
Cell-penetrating peptides (CPPs) are cationic peptide sequences from various proteins (protein transduction domains) that can convey large molecules and particles across plasma membranes (Jain et al., 2007).
H+-coupled oligopeptide transporters PEPT1 and PEPT2 are upregulated in many tumour cells (Nakanishi et al., 1997; Gong et al., 2017). Labelled oligopeptides could be used to detect tumours, and have been proposed to be used as boron carriers in BNCT (Miyabe et al., 2019).
Small peptides and proteins are mainly eliminated from circulation by the kidneys by excretion into urine and via peritubular reabsorption and intracellular degradation. While the amino acids are released from lysosomes to the blood, retention of the radionuclides in tubular cells leads to increased radiation dose, which often limits the maximum dose that can be administered in radiotherapy. Megalin (Low-density lipoprotein-related protein 2, LRP2) is a membrane-associated endocytic receptor, which has a central role in clathrin-mediated endocytosis and metabolism of proteins in renal proximal tubular endothelial cells (De et al., 2014). Renal uptake of peptides can be inhibited by co-administered albumin fragments (Vegt et al., 2008 and 2010). On the other hand, peptides can be used to target drug delivery into renal tubules (Wischnjow et al., 2016). Megalin is also present in neurons and brain capillaries, especially in the choroid plexus, suggesting that megalin may facilitate the transport of peptides and proteins between blood and cerebrospinal fluid.
Bumbaca B, Li Z, Shah DK. Pharmacokinetics of protein and peptide conjugates. Drug Metab Pharmacokinet. 2019; 34(1): 42-54. doi: 10.1016/j.dmpk.2018.11.001.
Chatalic KL, Kwekkeboom DJ, de Jong M. Radiopeptides for imaging and therapy: a radiant future. J Nucl Med. 2015; 56(12): 1809-1812. doi: 10.2967/jnumed.115.161158.
Fani M, Maecke HR. Radiopharmaceutical development of radiolabelled peptides. Eur J Nucl Med Mol Imaging 2012; 39(Suppl 1): S11-S30.
Jackson IM, Scott PJH, Thompson S. Clinical applications of radiolabeled peptides for PET. Semin Nucl Med. 2017; 47(5): 493-523. doi: 10.1053/j.semnuclmed.2017.05.007.
Kastin AJ (ed.): Handbook of Biologically Active Peptides, 2nd ed., Academic Press, 2013. eISBN: 9780123850966.
Opalinska M, Hubalewska-Dydejczyk A, Sowa-Staszczak A. Radiolabeled peptides: current and new perspectives. Q J Nucl Med Mol Imaging 2017; 61(2): 153-167.
Roivainen A, Jalkanen S, Nanni C. Gallium-labelled peptides for imaging of inflammation. Eur J Nucl Med Mol Imaging 2012; 39(Suppl 1): S68-S77. doi: 10.1007/s00259-011-1987-6.
Sun X, Li Y, Liu T, Li Z, Zhang X, Chen X. Peptide-based imaging agents for cancer detection. Adv Drug Deliv Rev. 2017; 110-111: 38-51. doi: 10.1016/j.addr.2016.06.007.
Zhao N, Qin Y, Liu H, Cheng Z. Tumor-targeting peptides: ligands for molecular imaging and therapy. Anticancer Agents Med Chem. 2018; 18(1): 74-86. doi: 10.2174/1871520617666170419143459.
Updated at: 2019-04-23
Created at: 2017-10-28
Written by: Vesa Oikonen