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Synthesis and SAR of ⁹⁹mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2013 Mar 01; Vol. 23 (5), pp. 1557-63. Date of Electronic Publication: 2012 Sep 13. - Publication Year :
- 2013
-
Abstract
- Prostate specific membrane antigen (PSMA) is recognized as an attractive molecular target for the development of radiopharmaceuticals to image and potentially treat metastatic prostate cancer. A series of novel (99m)Tc/Re-tricarbonyl radiolabeled PSMA inhibitors were therefore synthesized by the attachment of glutamate-urea-lysine (Glu-urea-Lys) and glutamate-urea-glutamate (Glu-urea-Glu) pharmacophore to single amino acid chelate (SAAC) where the SAAC ligand was either bis(pyridin-2-ylmethyl)amino (DPA), bis((1-methyl-1H-imidazol-2-yl)methyl)amino (NMI), bis((1-(carboxymethyl)-1H-imidazol-2-yl)methyl)amino (CIM) or bis((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino (TIM). The in vitro binding affinity of the rhenium complexes was evaluated using PSMA-expressing human prostate cancer LNCaP cells. IC(50) values ranged from 3.8 ± 2 to >2000 nM. A linker between the SAAC chelate and pharmacophore was required for high affinity binding. However, extending the length of the linker did not substantially improve binding. PSMA binding was also influenced by the nature of the SAAC chelate. One of the most potent compounds, 23b (IC(50)=4.8 ± 2.7 nM), was radiolabeled with technetium tricarbonyl ({(99m)Tc(CO)(3)}(+)) to afford the {(99m)Tc(CO)(3)}(+) complex in excellent yield and high purity. This effort has led to the identification of a diverse series of promising high affinity {(99m)Tc(CO)(3)}(+) radiolabeled PSMA inhibitors.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Cell Line, Tumor
Chelating Agents chemical synthesis
Chelating Agents pharmacokinetics
Chelating Agents pharmacology
Humans
Ligands
Male
Organotechnetium Compounds chemical synthesis
Organotechnetium Compounds pharmacokinetics
Organotechnetium Compounds pharmacology
Prostatic Neoplasms metabolism
Radionuclide Imaging
Radiopharmaceuticals chemical synthesis
Radiopharmaceuticals pharmacokinetics
Radiopharmaceuticals pharmacology
Structure-Activity Relationship
Tissue Distribution
Chelating Agents chemistry
Kallikreins antagonists & inhibitors
Organotechnetium Compounds chemistry
Prostate-Specific Antigen antagonists & inhibitors
Prostatic Neoplasms diagnostic imaging
Radiopharmaceuticals chemistry
Rhenium chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 23
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 23333070
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.09.014