Abstract
The high affinity and specificity of peptides towards biological targets, in addition to their favorable pharmacological properties, has encouraged the development of many peptide-based pharmaceuticals, including peptide-based positron emission tomography (PET) radiopharmaceuticals. However, the poor in vivo stability of unmodified peptides against proteolysis is a major challenge that must be overcome, as it can result in an impractically short in vivo biological half-life and a subsequently poor bioavailability when used in imaging and therapeutic applications. Consequently, many biologically and pharmacologically interesting peptide-based drugs may never see application. A potential way to overcome this is using peptide analogues designed to mimic the pharmacophore of a native peptide while also containing unnatural modifications that act to maintain or improve the pharmacological properties. This review explores strategies that have been developed to increase the metabolic stability of peptide-based pharmaceuticals. It includes modifications of the C- and/or N-termini, introduction of d- or other unnatural amino acids, backbone modification, PEGylation and alkyl chain incorporation, cyclization and peptide bond substitution, and where those strategies have been, or could be, applied to PET peptide-based radiopharmaceuticals.
Highlights
Positron emission tomography (PET) is a nuclear medicine imaging technique for the non-invasive quantitative measurement of specific biochemical, physiological, and pharmacological processes in vivo [1]
The applicability of new peptide-based radiopharmaceuticals will be influenced to a large extent by their in vivo stability as the inherently poor in vivo stability of natural peptides is one of the biggest challenges in the development of peptide-based radiopharmaceuticals, especially as degradation of the peptide can lead to non-specific binding
There have been several strategies developed to avoid this by modifying natural peptides to enhance their metabolic stability and sometimes other pharmacological properties such as receptor affinity
Summary
Positron emission tomography (PET) is a nuclear medicine imaging technique for the non-invasive quantitative measurement of specific biochemical, physiological, and pharmacological processes in vivo [1]. PET imaging is achieved by administering a patient with a PET radiopharmaceutical which will localize into organs and/or tissues that express the desired biological target. The distribution of the PET radiopharmaceutical throughout the body can be imaged with a PET scanner and a diagnosis can be made. PET radiopharmaceuticals are biologically active molecules that are labeled with positron-emitting radionuclides such as fluorine-18, gallium-68, or copper-64. A key component of a PET radiopharmaceutical is the targeting entity, which is designed to possess a pharmacophore that has high affinity and specificity towards a desired biological target present in an organ and/or tissue that is associated with a specific disease or malignancy [3]. 22 of of 24 biologically active small molecules, as is the case for the most widely used PET radiopharmaceutical as is the case for most widely used PET [18 F]fluorodeoxyglucose [4]. In recent yearsradiopharmaceutical there has been a rapid development in the use in recent years there has been a rapid development in the use of targeting entities developed of targeting entities developed from biologics, such as peptides, proteins, antibodies, and antibody from biologics, peptides, proteins, antibodies, fragments for thesuch use as as PET radiopharmaceuticals [5,6,7].and antibody fragments for the use as PET radiopharmaceuticals [5,6,7]
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