Microscopic view of PSMA ligands targeting prostate cancer cells.

PSMA Ligands: The Future of Prostate Cancer Theranostics?

Soraya Malik in Health & Wellness November 2025 • 5 min read.

"Exploring 2-Aminoadipic Acid-C(O)-Glutamate Based Ligands for Targeted Prostate Cancer Treatment and Imaging"

Prostate cancer (PCa) remains a significant health challenge, ranking as one of the most frequently diagnosed cancers and a leading cause of death among men in the United States. The financial burden of managing PCa is substantial, highlighting the urgent need for more effective diagnostic and therapeutic strategies. Prostate-specific membrane antigen (PSMA) has emerged as a promising target because PCa cells highly overexpress it compared to normal cells. This overexpression is often linked to poorer disease outcomes, making PSMA an attractive focus for targeted interventions.

Researchers have been diligently developing PSMA ligands, including antibodies, peptides, aptamers, and small molecules, to deliver imaging agents for cancer diagnosis. Among these, small molecules offer advantages such as ease of synthesis, reduced immunogenicity, and rapid clearance from normal tissues. Early efforts in 2001 introduced urea-based PSMA inhibitors, which have since become a cornerstone for PSMA targeting due to their high affinity and synthetic accessibility. Recent clinical trials utilizing 18F or 68Ga-labeled PSMA ligands for PET imaging have shown promise but also revealed off-target uptake in the kidneys and salivary glands.

Addressing these challenges, scientists are exploring ways to enhance compounds' hydrophilicity to promote faster clearance from non-target tissues. Despite extensive research on PSMA ligands, the impact of varying the length of the amino acid moiety—beyond the essential glutamate—on PSMA affinity remains largely unexplored. In this context, the research investigates 2-aminoadipic acid as a novel building block to optimize chain length and improve interactions with the S1 hydrophobic pocket of PSMA, potentially reducing the required dosage and enhancing image resolution.

Unlocking PSMA Potential: How Novel Ligands Are Changing the Game

Microscopic view of PSMA ligands targeting prostate cancer cells.

The study focuses on 2-aminoadipic acid, a building block not previously utilized in PSMA ligands, to explore its potential in enhancing PSMA affinity. Researchers synthesized fluorinated PSMA ligands incorporating 2-aminoadipic acid to improve imaging resolution, leveraging the benefits of the radionuclide 18F. The synthesis involved protecting the distal carboxyl group of L-2-aminoadipic acid with benzylation, followed by coupling with an isocyanate. Subsequent steps included protecting the free carboxyl group as a tert-butyl ester and deprotecting the benzyl ester through hydrogenation.

The amidation of compound 6 yielded the desired amides 7-15, which were then purified using preparative high-performance liquid chromatography (HPLC). The chemical structures were confirmed via NMR and LCMS-IT-TOF, ensuring a purity level exceeding 95% for all tested compounds, as verified by analytical HPLC. The radioenzymatic assay determined the inhibition constants (IC50 values) of these compounds against the PSMA enzyme, using [3H]NAAG as a substrate. Key findings include:

Benzylamide Derivatives: The IC50 values for benzylamide derivatives 7a-7c were nearly identical, indicating that the position of the fluorine atom does not affect their potency.
Methyl Group Introduction: Introducing a methyl group on the amide nitrogen of 7a and 7b increased their potency for PSMA (compounds 8a and 8b).
Benzylic Position Methylation: Compounds 9a and 9b, with a methyl group attached to the benzylic position, exhibited significantly lower inhibitory affinity for PSMA compared to 7a and 8a. This decrease is attributed to steric hindrance, where the methyl group clashes with the side chain of Arg463, disrupting the insertion of the inhibitor ring into the S1 hydrophobic pocket.
Pyridine Ring Substitution: Compound 10, where the benzene ring is replaced with a pyridine ring, showed marginally lower affinity compared to 7a.

To visualize the binding mode of the new PSMA ligands, the crystal structure of the PSMA/7a complex was determined, revealing that the aromatic ring of 7a inserts into the S1 hydrophobic pocket, enhancing its inhibitor potency through interactions contributed by the distal aromatic ring. The series of compounds 11-13, which have a shortened P1 linker, demonstrated sub-nanomolar IC50 values, indicating that aminoadipic serves as an excellent substitute for lysine in urea-based compounds. The anilides 11-13 displayed higher affinities than the benzylamides 7-10, suggesting that the distance between the aromatic ring and the urea moiety in the former is more suitable for strong interactions within the PSMA’s internal pocket. Methylated anilides 12 and 13b showed enhanced affinity compared to their N-H counterparts, with 13b exhibiting the highest inhibitory activity (IC50 = 0.075 nM) among all synthesized PSMA ligands.

The Future of PSMA Ligands in Prostate Cancer Treatment

In conclusion, the research successfully designed and synthesized PSMA ligands derived from 2-aminoadipic acid, a novel building block for PSMA ligands. Among the synthesized ligands, compound 13b exhibited the highest inhibitory activity for PSMA. The labeling methods previously described for [18F]DCFPyL and [18F]PSMA-1007 offer strong support for the potential preparation of [18F]13b. A branching moiety can be attached to the amide function of 13b, enabling the modulation of physicochemical and pharmacokinetic properties of the next-generation compounds while preserving the high affinity of the original compound for PSMA.

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This article is based on research published under:

DOI-LINK: 10.1021/acsmedchemlett.8b00318, Alternate LINK

Title: 2-Aminoadipic Acid–C(O)–Glutamate Based Prostate-Specific Membrane Antigen Ligands For Potential Use As Theranostics

Subject: Organic Chemistry

Journal: ACS Medicinal Chemistry Letters

Publisher: American Chemical Society (ACS)

Authors: Ryo Nakajima, Zora Nováková, Werner Tueckmantel, Lucia Motlová, Cyril Bařinka, Alan P. Kozikowski

Published: 2018-10-24

Everything You Need To Know

What is PSMA and why is it a promising target for prostate cancer theranostics?

Prostate-specific membrane antigen (PSMA) is a protein that is highly overexpressed on the surface of prostate cancer cells compared to normal cells. This overexpression is often associated with more aggressive disease and poorer patient outcomes, making PSMA an attractive target for diagnostic imaging and targeted therapies. The development of PSMA ligands, such as small molecules based on urea, allows for specific targeting of prostate cancer cells. These ligands can be labeled with imaging agents or therapeutic radionuclides to visualize or treat the cancer.

What role does 2-aminoadipic acid play in the development of novel PSMA ligands, and how does it compare to other building blocks?

2-Aminoadipic acid is a novel building block used in the synthesis of PSMA ligands. It is incorporated into the ligand structure to optimize the chain length and improve interactions with the S1 hydrophobic pocket of PSMA. By using 2-aminoadipic acid, researchers aim to enhance the ligand's affinity for PSMA, potentially reducing the required dosage and improving the resolution of imaging. In contrast to lysine, aminoadipic acid serves as an excellent substitute.

What key structural modifications to the 2-aminoadipic acid-based PSMA ligands were found to influence their inhibitory activity?

The study found that specific structural modifications to the 2-aminoadipic acid-based PSMA ligands significantly influenced their inhibitory activity against PSMA. For example, introducing a methyl group on the amide nitrogen of certain compounds increased their potency, while attaching a methyl group to the benzylic position decreased their affinity due to steric hindrance. The most potent compound, 13b, exhibited the highest inhibitory activity with an IC50 of 0.075 nM. Also, the aromatic ring inserts into the S1 hydrophobic pocket enhancing its inhibitor potency.

How does the crystal structure of the PSMA/7a complex inform our understanding of PSMA ligand binding and potency?

The crystal structure of the PSMA/7a complex revealed that the aromatic ring of compound 7a inserts into the S1 hydrophobic pocket of PSMA, enhancing its inhibitor potency through interactions contributed by the distal aromatic ring. This finding confirms the importance of the aromatic ring's positioning and interaction with the hydrophobic pocket for achieving high-affinity binding. Visualizing these interactions at the molecular level helps researchers understand the key structural features that drive potent PSMA inhibition and informs the design of even more effective ligands.

What are the future directions for PSMA ligands in prostate cancer treatment, and how are researchers working to improve their properties?

The future of PSMA ligands in prostate cancer theranostics involves further optimization of their physicochemical and pharmacokinetic properties while maintaining high affinity for PSMA. Researchers are exploring the attachment of branching moieties to the amide function of compounds like 13b to modulate these properties. The successful preparation of [18F]13b is supported by labeling methods previously described for [18F]DCFPyL and [18F]PSMA-1007, suggesting its potential use in PET imaging. These advancements aim to develop next-generation PSMA ligands with improved targeting, imaging resolution, and therapeutic efficacy.