Design, Synthesis, and Evaluation of Linker-Optimised PSMA-Targeting Radioligands

Abstract

Prostate-specific membrane antigen (PSMA) is overexpressed in the majority of prostate cancer cells and is considered to be an important target for the molecular imaging and therapy of prostate cancer. Herein, we present the design, synthesis, and evaluation of 11 PSMA-binding radioligands with modified linker structures, focusing on the relationship between molecular structure and targeting properties. The linker design was based on 2-naphthyl-L-alanine-tranexamic acid, the linker structure of PSMA-617. X-ray crystal-structure analysis of PSMA and structure-based design were used to generate the linker modifications, suggesting that substitution of tranexamic acid could lead to interactions with Phe546, Trp541, and Arg43 within the binding cavity. After synthesis through SPPS, analogues were labelled with indium-111 and evaluated in vitro for their specific binding, affinity, and cellular retention. Selected compounds were further evaluated in vivo in PSMA-expressing tumour-bearing mice. Based on the results, 2-naphthyl-L-alanine appears to be crucial for good targeting properties, whereas tranexamic acid could be replaced by other substituents. [111In]In-BQ7859, consisting of a 2-naphthyl-L-alanine-L-tyrosine linker, demonstrated favourable targeting properties. The substitution of tranexamic acid for L-tyrosine in the linker led to an improved tumour-to-blood ratio, highlighting [111In]In-BQ7859 as a promising PSMA-targeting radioligand.

Synthesis and Preclinical Evaluation of PSMA-Targeted 111In-Radioconjugates Containing a Mitochondria-Tropic Triphenylphosphonium Carrier

“…Nevertheless, the metal complexation and the presence of the Gly-Gly-Gly linker showed some influence on the binding affinity of the compounds. To better understand these effects, in silico approaches based on molecular docking and molecular dynamics simulations are a good option, as previously reported by other authors for different families of PSMA inhibitors, 39,50,51 taking advantage of the availability of the X-ray structure of the PSMA protein. 52 However, these in silico studies were outside the scope of the present work.…”

Synthesis, Preclinical Evaluation, and First-in-Human PET Study of [68Ga]-Labeled Biphenyl-Containing PSMA Tracers

“…To address the challenges associated with PSMA radioligands, researchers have proposed multiple chemical optimization strategies. These approaches involve modifying the linker between the targeting moiety and the pharmacophore to enhance binding affinity. − Additionally, incorporating albumin-binding moieties such as iodobenzylbutyric acid, ibuprofen, and Evans blue has been explored to extend the drug’s serum half-life. − Furthermore, investigating new isotopes for diagnostic and therapeutic purposes, such as 64 Cu, 89 Zr, and 111 In for imaging as well as 90 Y, 225 Ac, and 212 Pb for therapy, offers promising avenues for improvement. Increasing the number of pharmacophores is another effective strategy that has been shown to significantly enhance compound affinity.…”

Prostate specific membrane antigen binding radiopharmaceuticals: Current data and new concepts

“…All the PSMA targeted agents in therapeutic trials to date can be readily classified in terms of small molecules or antibodies. The small molecules typically have four components, a PSMA binding moiety, a linker, a chelator, and an isotope (5)(6)(7). All the antibodies in current development are targeted to bind the extracellular domain of PSMA (at a different site than the small molecules).…”

“…The linker is a key component that affects tumor targeting, pharmacokinetics, and cellular uptake. Interestingly, various linker/chelator moieties have quite distinct internalization ratios (5)(6)(7). Thus the combination of linkers and chelators are critical to the PSMA small molecules and must be carefully considered in design considerations.…”