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 for peptide-receptor radionuclide therapy (PRRT).

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 HER3 (Larimer 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.

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Updated at: 2023-10-25
Created at: 2017-10-28
Written by: Vesa Oikonen