Synthesis and evaluation of novel radioiodinated PSMA targeting ligands for potential radiotherapy of prostate cancer.
Bioorg Med Chem
; 28(5): 115319, 2020 03 01.
Article
em En
| MEDLINE
| ID: mdl-32001090
ABSTRACT
Radioligand therapy (RLT) using prostate-specific membrane antigen (PSMA) targeting ligands is an attractive option for the treatment of Prostate cancer (PCa) and its metastases. We report herein a series of radioiodinated glutamate-urea-lysine-phenylalanine derivatives as new PSMA ligands in which l-tyrosine and l-glutamic acid moieties were added to increase hydrophilicity concomitant with improvement of in vivo targeting properties. Compounds 8, 15, 19a/19b and 23a/23b were synthesized and radiolabeled with 125I by iododestannylation. All iodinated compounds displayed high binding affinities toward PSMA (IC50 = 1-13 nM). In vitro cell uptake studies demonstrated that compounds containing an l-tyrosine linker moiety (8, 15 and 19a/19b) showed higher internalization than MIP-1095 and 23a/23b, both without the l-tyrosine linker moiety. Biodistribution studies in mice bearing PC3-PIP and PC3 xenografts showed that [125I]8 and [125I]15 with higher lipophilicity exhibited higher nonspecific accumulations in the liver and intestinal tract, whereas [125I]19a/19b and [125I]23a/23b containing additional glutamic acid moieties showed higher accumulations in the kidney and implanted PC3-PIP (PSMA+) tumors. [125I]23b displayed a promising biodistribution profile with favorable tumor retention, fast clearance from the kidney, and 2-3-fold lower uptake in the liver and blood than that observed for [125I]MIP-1095. [125/131I]23b may serve as an optimal PSMA ligand for radiotherapy treatment of prostate cancer over-expressing PSMA.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenilalanina
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Neoplasias da Próstata
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Ureia
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Ácido Glutâmico
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Compostos Radiofarmacêuticos
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Lisina
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos