title: Synthesis and SAR of ⁹⁹mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates.
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.
authors: Molecular Insight Pharmaceuticals, Inc., 160 Second Street, Cambridge, MA 02142, United States.
authors: Genliang
authors: G
authors: Lu
authors: Kevin P
authors: KP
authors: Maresca
authors: Shawn M
authors: SM
authors: Hillier
authors: Craig N
authors: CN
authors: Zimmerman
authors: William C
authors: WC
authors: Eckelman
authors: John L
authors: JL
authors: Joyal
authors: John W
authors: JW
authors: Babich
mesh_terms: D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D008024:Ligands; D008297:Male; D015609:Organotechnetium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D012211:Rhenium / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D008024:Ligands; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; D012211:Rhenium; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen