Paving the way for future PSMA inhibitors: insights from comparative preclinical evaluations of structure modifications

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00098892%3A_____%2F25%3A10159448" target="_blank" >RIV/00098892:_____/25:10159448 - isvavai.cz</a>

Result on the web

<a href="https://ejnmmipharmchem.springeropen.com/articles/10.1186/s41181-025-00389-w" target="_blank" >https://ejnmmipharmchem.springeropen.com/articles/10.1186/s41181-025-00389-w</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1186/s41181-025-00389-w" target="_blank" >10.1186/s41181-025-00389-w</a>

Result language

angličtina

Original language name

Paving the way for future PSMA inhibitors: insights from comparative preclinical evaluations of structure modifications

Original language description

Background: Prostate-specific membrane antigen (PSMA) is an established target for the imaging and treatment of prostate cancer. This study focused on the preclinical evaluation of three novel PSMA inhibitors—P15, P16, and P19—which were structurally modified compared to the clinically used PSMA-617. Two main strategies were pursued: a chemical approach following the so-called reversed synthetic strategy, and the replacement of the naphthyl-based linker moiety with an analogous diphenyl-based moiety. The aim was to assess the impact of these modifications on physicochemical properties, in vitro behaviour, and in vivo pharmacokinetics following radiolabelling with ⁶⁸Ga. Results: Radiolabelling of all three novel compounds with ⁶⁸Ga resulted in high radiochemical purity above 98% under physiological pH conditions and above 97% during stability testing in human plasma. All compounds exhibited hydrophilic characteristics based on partition coefficient measurements. Notable differences were observed in plasma protein binding, with P15 and P16 showing significantly lower binding compared to PSMA-617 and P19. In vitro assays using LNCaP prostate cancer cells demonstrated similar cellular uptake and internalization across all tested compounds. In vivo evaluation using Positron Emission Tomography/Computed Tomography (PET/CT) imaging in LNCaP tumour-bearing mice confirmed the tumour-targeting ability of all three inhibitors. These findings were further supported by biodistribution studies, which highlighted efficient and specific accumulation in tumour tissue. Among the tested compounds, P19 demonstrated the most promising overall profile in terms of stability, binding characteristics, and tumour uptake. Conclusions: The stereochemical modifications in the linker region significantly influenced the in vitro and in vivo behaviour of the PSMA inhibitors. Despite similar cellular uptake, differences in plasma protein binding and pharmacokinetics were evident. Among the three novel compounds, P19 emerged as a particularly promising candidate for further investigation, also indicating that the diphenyl moiety might serve as a favourable linker building block in analogy to the naphthyl moiety. Our observations suggest potential not only for diagnostic imaging with ⁶⁸Ga, but also for therapeutic applications using 177Lu, which offers a longer half-life suitable for delayed imaging and treatment intervals in prostate cancer management.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30107 - Medicinal chemistry

Project

<a href="/en/project/EH22_008%2F0004644" target="_blank" >EH22_008/0004644: Saving lives through research in early cancer detection and prevention: Molecular, genomic and societal factors</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

EJNMMI Radiopharmacy and Chemistry

ISSN

—

e-ISSN

2365-421X

Volume of the periodical

10

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

18

Pages from-to

63

UT code for WoS article

001582426600002

EID of the result in the Scopus database

2-s2.0-105017795333