Affinity probes based on small-molecule inhibitors for tumor imaging

Abstract

Methods for molecular imaging of target areas, including optical imaging, radionuclide imaging, magnetic resonance imaging and other imaging technologies, are helpful for the early diagnosis and precise treatment of cancers. In addition to cancer management, small-molecule inhibitors are also used for developing cancer target probes since they act as the tight-binding ligands of overexpressed proteins in cancer cells. This review aims to summarize the structural designs of affinity probes based on small-molecule inhibitors from the aspects of the inhibitor, linker, dye and radionuclide, and discusses the influence of the modification of these structures on affinity and pharmacokinetics. We also present examples of inhibitor affinity probes in clinical applications, and these summaries will provide insights for future research and clinical translations.

Keywords: affinity probe; inhibitor; near-infrared; radiotracer; tumor imaging.

Scheme 1

The classifications of AfPIs and their features. In this review, we classified AfPIs into visible-region, near-infrared, radiolabeled and dual-modal probes, and introduced them from three aspects: the inhibitors, linkers and dyes or radionuclides.

Figure 1

Some structures of traditional visible AfPIs and their parent inhibitors (Blue, inhibitor structure; green and red, fluorophores).

Figure 2

The quenching mechanism of PeT effects and AfPIs are designed based on PeT effects. When probes do not bind to the proteins, the fluorescence is quenched by Pet effects. After binding to proteins, the folded structure is open and the PeT effect disappears, resulting in the release of fluorescence (HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital).

Figure 3

Structures of clorgyline and clorgyline-derived AfPIs (Blue, inhibitor structure; red fluorophores). (A) Molecular docking shows that clorgyline forms hydrogen bonds between its chlorine atoms and the Cys323 and Thr326 residues of MAO-A (PDB ID: 2BXR).

Figure 4

Structures of the PSMA inhibitor and its derived AfPIs (Blue, GLU units Green, 2-nitroimidazole group). (A) Schematic of bivalent and dual-targeted AfPIs for prostate cancer (PC, prostate cancer).

Figure 5

Conjugations between inhibitors and NIR fluorophores. (A) Conducting molecular docking analysis of CYP1B1 inhibitor and its target before conjugation to avoid the loss of affinity. Reprinted with permission (42). Copyright 2018 American Chemical Society. (B) The common types of NIR fluorophores. (C) Conjugating with the heptamethine cyanine dye MHI148 can improve the antitumor effect of the MAO-A inhibitor isoniazid. Reprinted with permission (43). Copyright 2018 Elsevier. (D) The conjugation of FTS with cancer-targeting heptamethine cyanine dye improved its pharmacological profile. Reprinted with permission (44). Copyright 2017 American Chemical Society. (E) Molecular docking results demonstrated a 20 Å tunnel region in PSMA. Reprinted with permission (45). Copyright 2020 Elsevier.

Figure 6

Some structures of radiolabeled AfPIs with nonmetallic radionuclide labels(Red: radionuclide labels). (A, B) The molecular docking result of [¹⁸F] labeled TrkA inhibitor with TrkA protein showed that the labeled inhibitor could bind with Trk. Reprinted with permission (84). Copyright 2018 American Chemical Society.