Peptides in molecular imaging and radiopharmaceuticals

Molecular imaging probes are important tools in nuclear medicine. Early disease detection, characterization and monitoring of disease progression and therapeutic responses are the main applications.

The use of imaging probes based on radiolabeled small molecules or macromolecules has been limited by low specificity (small molecules) or limited target permeability (monoclonal antibodies). Peptides have been increas­ingly considered as imaging probes, due to their distinctive advantages over small molecules or macromolecules. Peptides can act as a radionuclide carrier in Peptide Receptor Radionuclide Therapy (PRRT).

Due to their ability to bind to different receptors and also being part of several biochemical pathways, peptides act as potential diagnostic tools and biomarkers in disease (e.g. cancer) progression. Peptide receptors such as somatostatin (SST), integrin, gastrin-releasing peptide (GRP), cholecystokinin (CCK), neurotensin (NT), glucagon-like peptide-1 (GLP-1), and neuropeptide-Y (NPY) receptors have been successfully identified and characterized for tumor receptor imaging. Additionally, a number of bioactive peptides and peptide hormones have been discovered through combinatorial peptide chemistry and phage display technology. Such peptides generally have high affinities and specificity for their target and are active at low nanomolar concentrations.

Peptide based Radiopharmaceuticals explained

Peptides could be directly or indirectly labeled with a wide range of imaging moieties by different chemistries for use as in vivo probes. Radionuclides attached to peptides have been employed for positron emission tomography (PET) or single photon emission computed tomography (SPECT). Near-infrared (NIR) fluorescent dyes or quantum dots attached to peptides can be used for optical imaging. Paramagnetic agents attached to peptides are used for magnetic resonance imaging (MRI). In all these techniques the role of the peptide is to carry the probe to the specific receptor target.

Most neuroendocrine tumors (NETs) feature a strong overexpression of somatostatin receptors, mainly of subtype 2 (sst2). Currently, five somatostatin receptor subtypes (sst) are known (sst1-5). The density of these receptors is vastly higher than on non-tumor tissue. Therefore, somatostatin receptors are attractive targets for delivery of radioactivity via radiolabeled somatostatin analogs. Introduced in the late 1980s, [111In-DTPA]-octreotide ([111In]-pentetreotide, OctreoScan®), the first available radiolabeled somatostatin analog, rapidly became the gold standard for diagnosis of sst-positive NETs. An octreotide scan or octreoscan is a type of scintigraphy used to find carcinoid and other types of tumors and to localize sarcoidosis. [111In-DTPA]-octreotide is a synthetic analog of somatostatin carrying a chelating moiety and radiolabeled with indium-111. Injected into a vein the tracer travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A radiation-measuring device detects the radioactive octreotide and produces images showing where the tumor is located in the body.

Figure 1: Radionuclide-labeled peptide binds to receptor on cancer cell surface and enters into the cell, followed by emission of radiation that destroys DNA and cancer cell.

Peptide receptor radionuclide therapy (PRRT) combines octreotide (or other somatostatin analogs) with a radionuclide (a radioactive isotope) to form highly specialized molecules called radiolabeled somatostatin analogs or radiopeptides. Radiolabeled somatostatin analogs generally comprise three main parts: a cyclic octapeptide (e.g., octreotide), a chelator (e.g., DTPA, DOTA), and a radionuclide (68Ga, 111In, 90Y, or 177Lu). These radiopeptides can be injected into a patient and will travel throughout the body binding to carcinoid tumor cells that have receptors for them. Once bound, these radiopeptides emit radiation and kill the tumor cells they are bound to (see Figure 1). A few examples of radiolabeled peptide in clinical trials are shown in Table 1.

Radiolabeled PeptidePeptide ReceptorIndication
111In-DTPA-octreotideSST-SomatostatinNeuroendocrine tumors
Nα-(1-deoxy-D-fructosyl)-Nε-(2-[18F]-fluoropropionyl)-Lys0,Tyr3-octreotate (18F-[Gluc-Lys]-TOCA)SST-SomatostatinNeuroendocrine tumors
[18F]-galacto-RGDIntegrinHead and neck cancer
[18F]-RGD-K5IntegrinVarious cancers
[99Tc]-Me2Gly-Ser-Cys-Gly-5Ava-Bombesin (7-14)([99Tc]-RP-527)GRPBreast cancer
[111In]-[DTPA-Lys40]-Exendin-4GLP-1Insulinoma

Table 1: Examples of radiolabeled peptide probes in clinical trials.

 

 

In addition to our thousands of catalog peptides, we offer comprehensive custom peptide synthesis services. If the peptide you require is not available at shop.www.bachem.com, please contact us.

References

Thundimadathil, J., Cancer treatment using peptides: current therapies and future prospects, J. Amino Acids 2012, ID 967347 (2012)

Lee, S. et al., Peptide-based probes for targeted molecular imaging, Biochemistry 49, 1364 (2010)

 

SOMATOSTATIN ANALOGS IN CANCER THERAPY

Apart from the use of peptidic LHRH agonists and antagonists for treating cancer, somatostatin analogs are the only approved cancer therapeutic peptides in the market. Potent agonists of somatostatin (SRIF) including octreotide (sandostatin) have been developed for the treatment of acromegaly, gigantism and thyrotropinoma associated with carcinoid syndrome, and diarrhea in patients with vasoactive intestinal peptide-secreting tumors (VIPomas). Lanreotide, another long-acting analog of somatostatin, is used in the management of acromegaly and symptoms caused by neuroendocrine tumors.

Most neuroendocrine tumors (NETs) feature a strong overexpression of somatostatin receptors, mainly of subtype 2 (sst2). Currently, five somatostatin receptor subtypes (sst) are known (sst1-5). The density of these receptors on tumor tissue is vastly higher than on healthy tissue. Therefore, sst are attractive targets for delivery of radionuclides employing appropriately modified somatostatin analogs. Introduced in the late 1980s by Sandoz, [111In-DTPA]-octreotide (pentetreotide, Octreoscan®), rapidly became the gold standard for diagnosis of sst-positive NETs. Numerous peptide-based tumor-imaging agents targeting sst have been developed over the past decades. Octreoscan® and NeoTect® (technetium-99m-labeled depreotide, cyclo(MePhe-Tyr-D-Trp-Lys-Val-Hcy(CH2CO- β-Dap-Lys-Cys-Lys-NH2)) are the only radiopeptide tracers on the market approved by the FDA. An octreotide scan or octreoscan is a scintigraphic method used to find carcinoids and other types of tumors and to localize sarcoidosis. DTPA-Octreotide, after radiolabeling with indium-111, is injected into a vein and travels through the bloodstream. The radioactive octreotide attaches to tumor cells that have receptors for somatostatin. A radiation-measuring device detects the radioactive octreotide, and generates images showing the precise location of the tumor in the body.

The principle also works in cancer therapy. Peptide receptor radionuclide therapy (PRRT) combines appropriately modified octreotide with a radionuclide, which will bind to carcinoid tumor cells with overexpressed somatostatin receptors. Once bound, the targeted radiation will kill the malignant cells the peptide is bound to.

The complex between radionuclide and peptide has to be stable, especially if the radiopeptide is used in therapy. Cyclic chelators as DOTA bind (radio)nuclides as 68Ga, 90Y, or 177Lu more tightly, so (Tyr3)-DOTA-octreotide (DOTATOC, edotreotide) can be used in diagnosis and therapy of NETs. This also holds true for the C-terminal acid, DOTA-octreotate (DOTATATE).

Figure 1: Chemical structure of DOTA-octreotate

 

Somatostatin agonists vary in receptor selectivity: Lanreotide shows high affinity for sst2 and somewhat less to sst5. Pasireotide, another SRIF agonist, binds less selectively and thus mimics the natural ligand more closely.