A Review on the Current State and Future Perspectives of [99mTc]Tc-Housed PSMA-i in Prostate Cancer

Abstract

Recently, prostate-specific membrane antigen (PSMA) has gained momentum in tumor nuclear molecular imaging as an excellent target for both the diagnosis and therapy of prostate cancer. Since 2008, after years of preclinical research efforts, a plentitude of radiolabeled compounds mainly based on low molecular weight PSMA inhibitors (PSMA-i) have been described for imaging and theranostic applications, and some of them have been transferred to the clinic. Most of these compounds include radiometals (e.g., ⁶⁸Ga, ⁶⁴Cu, ¹⁷⁷Lu) for positron emission tomography (PET) imaging or endoradiotherapy. Nowadays, although the development of new PET tracers has caused a significant drop in single-photon emission tomography (SPECT) research programs and the development of new technetium-99m (^99mTc) tracers is rare, this radionuclide remains the best atom for SPECT imaging owing to its ideal physical decay properties, convenient availability, and rich and versatile coordination chemistry. Indeed, ^99mTc still plays a relevant role in diagnostic nuclear medicine, as the number of clinical examinations based on ^99mTc outscores that of PET agents and ^99mTc-PSMA SPECT/CT may be a cost-effective alternative for ⁶⁸Ga-PSMA PET/CT. This review aims to give an overview of the specific features of the developed [^99mTc]Tc-tagged PSMA agents with particular attention to [^99mTc]Tc-PSMA-i. The chemical and pharmacological properties of the latter will be compared and discussed, highlighting the pros and cons with respect to [⁶⁸Ga]Ga-PSMA11.

Keywords: PSMA; SPECT; gallium-68; molecular imaging; nanoparticles; prostate cancer; target-specific; technetium-99m.

Figure 7

(A) Amino acids of the active site of the PSMA enzyme (GCPII) interacting with the ligand PSMA 1007 (PDB code 5O5T, in light-blue). S1 pocket (‘’non-pharmacophore pocket’’) with its arginine patch is indicated in green. It is specific for binding to the NAA (N-acetyl-aspartyl-) portion of NAAG (or the NAA-like- portion of PSMA-i) through polar or nonpolar interaction [112]. In orange is highlighted the S1′ pocket, which specifically binds C-terminal glutamate residue. S1 is a flexible funnel specific for negatively charged amino acids which improve the interaction between PSMA and their inhibitors; its flexibility enables the binding of a variety of groups, which are not essential to the determination of the affinity [113]. (B) The active site of the PSMA receptor in which amino acids deputy to stabilize zinc ions are colored in red, whereas the side chains of Arg463, Arg511 and Trp54, forming the “arene-binding site”, are colored in yellow. The latter define the entrance of GCPII [114]. The images are created using UCSF Chimera 1.14.

Figure 1

Word incidence rates of prostate cancer in 2020.

Figure 2

Graphical representation of the dual nature of PSMA biomarker. PSMA consists of three domains: an intracellular domain with 18 amino acids (light blue), a transmembrane region with 24 amino acids (purple), which inserts into the phospholipid bilayer, and a catalytic domain in which there are 707 amino acids (pink) containing the active site with two zinc ions. On the right side, it is possible to appreciate the zoom of the cavity of the active site with a generic PSMA-i ligand in which the portions of the inhibitor that interact with specific entities of the receptor pocket are highlighted (created in BioRender).

Figure 3

Chemical representation of selected labeled and unlabeled PSMA-i derivatives. PSMA-i pharmacophore is evidenced in color.

Figure 4

Protein expression of PSMA in cancer tissues, neovascularization of cancer, and healthy tissues, along with the RNA expression in healthy tissues, obtained by combined information from the Human Protein Atlas and data from the literature.

Figure 5

Representation of the biFuntional approach. By this approach, an RP can be described as mainly composed of two essential parts: the targeting vector, i.e., the molecule or macromolecule that drives the radiometal to the pertinent molecular target, and the chelating system (also known as the BiFuntional Chelator, (BFC) designed to promptly and robustly bind the metal radionuclide, preventing it’s in vivo leakage, and to carry another reactive group able to form a strong covalent bond with the targeting vector, thus yielding a kinetically and thermodynamically stable construct. These two parts are directly bound or are held together by an appropriate linker or pharmacokinetic modifier (PKM). The final compound (bioconjugate complex) is then obtained through the appropriate labeling procedure, which depends on the specific radiometal.

Figure 6

Chemical sketches of DUPA and PSMA-i. (A,B) Glu-Ureo-based PSMA inhibitors conjugated through a spacer (in orange) to a so-called Bifunctional Chelating Agent (BFCA).

Figure 8

Chemical representation of the Tc-moieties utilized in developing [^99mTc]Tc-housed PSMA-i.

Figure 9

General structure of the SAAC Lys-based bifunctional chelator and corresponding Re complexes.

Figure 10

Coating ligands and radiolabeled PSMA-i derivatized NPs designed by Felber and coworkers.

Figure 11

Putative structures of [^99mTc]Tc-tagged-PSMA-i under clinical investigation.

Figure 12

Schematic drawing of bimodal hybrid tracer based on fluorescent Cy5 dye.