Peptides can be used as imaging probes when they bind to receptors that tumors overexpress while normal tissue does not. This article reviews representative peptide families, including RGD, bombesin, somatostatin, VIP, CCK/gastrin, alpha-MSH, neurotensin, T140, and exendin-4. It also lists their…
Peptides carry out their biological activity by binding to matching receptors. In tumor imaging, the most useful peptides are those that recognize receptors that tumor cells overexpress while normal cells show only weakly or not at all. Because the receptor signal is concentrated at the tumor, the attached peptide can help reveal the disease site in vivo. Many peptides and their analogs have been identified for disease detection, and the representative examples below illustrate the range of receptor targets and molecular formats now available.
Tumor imaging depends on contrast. A peptide that binds to a receptor found abundantly on malignant cells but barely detectable on healthy tissue creates a strong signal where the tumor is located. This explains why receptor overexpression is such an important criterion for peptide-based imaging agents.
RGD is a tripeptide that binds specifically to integrin receptors. Integrins are built from two subunits, alpha and beta. Among the integrin family, alphaVbeta3 plays a major role in tumor angiogenesis and metastasis. During angiogenesis, these receptors are overexpressed on endothelial cells but are barely detectable in most normal organs. As a result, they are widely used in diagnostic imaging.
The single-letter sequence for RGD is H2N-RGD-OH, and the three-letter sequence is H2N-Arg-Gly-Asp-OH. It contains 3 amino acids, has the molecular formula C12H22N6O6, and an average molecular weight of 346.34. The three-letter code names each residue directly, with Arg standing for arginine, Gly for glycine, and Asp for aspartic acid.
Representative RGD-related products include:
Bombesin and its related peptides come from amphibians and form a neuropeptide family with multiple physiological effects. These effects include exocrine and endocrine secretion, thermoregulation, sucrose regulation, and cell growth. Bombesin-like peptide receptors have four subtypes: neuromedin B receptor, bombesin receptor subtype 3, gastrin-releasing peptide receptor GRPR , and bombesin receptor subtype 4. These receptors are overexpressed in various tumors, including breast cancer, ovarian cancer, and gastrointestinal stromal tumors.
Representative bombesin and analog products include:
Gastrin-releasing peptide products in the same source list include:
Somatostatins are naturally occurring cyclic peptide hormones made of either 14 or 28 amino acids. They inhibit the secretion of insulin, glucagon, and several other hormones. Their biological effects are mediated through high-affinity somatostatin receptors, or SSTRs, of which there are five subtypes: SSTR1 through SSTR5. These receptors are overexpressed in a variety of neuroendocrine tumors, including pancreatic neuroendocrine tumors, small cell lung cancer, and thyroid carcinoma. Synthetic somatostatin analogs are therefore widely used in imaging and therapy of tumors that express these receptors.
Representative somatostatin and analog products include:
Vasoactive intestinal peptide, or VIP, is a neuropeptide made of 28 amino acids. It promotes vasodilation and also stimulates cell growth and proliferation through cell surface receptor-mediated signaling pathways. Its effects are primarily controlled by two receptor subtypes, VPAC1 and VPAC2. VIP receptors are highly expressed in a number of tumors, including brain tumors, pancreatic adenocarcinomas, and neuroendocrine tumors. The article also notes that VIP is considered a potential therapeutic agent, but toxicity may occur even at sub-microgram doses.
The single-letter sequence for VIP is H2N-HSDAVFTDNYTRLRKQMAVKKYLNSILN-OH, and the three-letter sequence is H2N-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-OH. It has 28 amino acids, the molecular formula C147H237N43O43S1, and an average molecular weight of 3326.78.
Representative VIP products include:
Cholecystokinin, or CCK, and gastrin are structurally and functionally related peptides that act in the gastrointestinal tract and central nervous system. They share an identical sequence in their bioactive region and differ only in the site of tyrosine sulfation, which is position 6 in gastrin and position 7 in CCK. Three CCK receptors have been identified: CCK1, CCK2, and CCK2i4sv, all belonging to the G protein-coupled receptor GPCR superfamily. Among these, the CCK2/gastrin receptor is frequently implicated in human cancers such as ovarian stromal tumors and astrocytomas.
The single-letter sequence given for the CCK/gastrin peptide is H2N-D-sTyr-MGWMDF-OH, and the three-letter sequence is H2N-Asp-Tyr SO3H -Met-Gly-Trp-Met-Asp-Phe-OH. It has 8 amino acids, the molecular formula C49H61N9O17S3, and an average molecular weight of 1144.25.
Alpha-melanocyte-stimulating hormone, or alpha-MSH, is a linear tridecapeptide responsible mainly for regulating skin pigmentation. Alpha-MSH and its analogs bind with very high affinity to the melanocortin-1 receptor, or MC-1R, which is expressed in over 80% of human melanoma metastases. Because of this, alpha-MSH is widely used as a carrier for targeted imaging and radiotherapy of melanoma.
The single-letter sequence for alpha-MSH is H2N-SYSMEHFRWGKPV-OH, and the three-letter sequence is H2N-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-OH. It has 13 amino acids, the molecular formula C75H106N20O19S1, and an average molecular weight of 1623.83.
Representative melanocyte-stimulating hormone products include:
Neurotensin is described in the article as a peptide consisting of 13 amino acids, while its listed sequence and properties give 12 amino acids. It acts on neurotensin receptors that have been identified in various tumors, such as ductal pancreatic adenocarcinoma, small-cell lung carcinoma, and medullary thyroid carcinoma. Neurotensin is therefore considered a highly promising candidate for cancer imaging applications.
The single-letter sequence for neurotensin is Pyr-LYENKPRRPYIL-OH, and the three-letter sequence is Pyr-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH. Its molecular formula is C78H121N21O20, and its average molecular weight is 1672.92.
Representative neurotensin and related products include:
T140 is a peptide made of 14 amino acids plus one disulfide bond. It acts as an antagonist of chemokine receptor 4, or CXCR4. Derivatives of T140 have been widely used as imaging agents that target CXCR4. Its single-letter sequence is H2N-RR-2Nal-CYRKkPYR-Cit-CR-OH, and its three-letter sequence is H2N-Arg-Arg-2Nal-Cys-Tyr-Arg-Lys-DLys-Pro-Tyr-Arg-Cit-Cys-Arg-OH. The molecular formula is C90H143N33O18S2, and the average molecular weight is 2039.44.
Exendin-4 is a peptide hormone consisting of 39 amino acids. It shares 50% sequence homology with the natural glucagon-like peptide-1, or GLP-1, and has been identified as an agonist of the GLP-1 receptor. The article notes that exendin-4 has clinical relevance, though the available text is cut off before the full clinical description is given.
Peptides referenced: KPV, Exenatide, VIP (Vasoactive Intestinal Peptide), Octreotide, Lanreotide, Pasireotide, Somatostatin, Glucagon.
Related reading: Macrocyclic Peptide Drugs: Structures, Pipelines and Oral Prospects, Six biocatalytic strategies for enzymatic oligopeptide synthesis, Enzymatic Routes to Oligopeptide Synthesis: A Technical Overview, Solid-Phase Peptide Synthesis: Resins and Working Protocols.