Radiohalogenated Prostate-Specific Membrane Antigen (PSMA)-Based Ureas as Imaging Agents for Prostate Cancer

• Published in: Journal of medicinal chemistry 2008-12, Vol.51 (24), p.7933-7943
• Main Authors: Chen, Ying, Foss, Catherine A, Byun, Youngjoo, Nimmagadda, Sridhar, Pullambhatla, Mrudula, Fox, James J, Castanares, Mark, Lupold, Shawn E, Babich, John W, Mease, Ronnie C, Pomper, Martin G
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - chemistry; Animals; Antigens, Surface - biosynthesis; Antigens, Surface - chemistry; Binding Sites; Biological and medical sciences; Chemistry, Pharmaceutical - methods; Computational Biology - methods; Contrast media. Radiopharmaceuticals; Diagnostic Imaging - instrumentation; Diagnostic Imaging - methods; Drug Design; Glutamate Carboxypeptidase II - biosynthesis; Glutamate Carboxypeptidase II - chemistry; Humans; Male; Medical sciences; Models, Molecular; Molecular Conformation; Pharmacology. Drug treatments; Prostatic Neoplasms - metabolism; Protein Binding; Radiopharmaceuticals - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801055h

To extend our development of new imaging agents targeting the prostate-specific membrane antigen (PSMA), we have used the versatile intermediate 2-[3-(5-amino-1-carboxy-pentyl)-ureido]-pentanedioic acid (Lys-C(O)-Glu), which allows ready incorporation of radiohalogens for single photon emission computed tomography (SPECT) and positron emission tomography (PET). We prepared 2-[3-[1-carboxy-5-(4-[125I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid ([125I]3), 2-[3-[1-carboxy-5-(4-[18F]fluoro-benzoylamino)-pentyl]-ureido]-pentanedioic acid ([18F]6), and 2-(3-[1-carboxy-5-[(5-[125I]iodo-pyridine-3-carbonyl)-amino]-pentyl]-ureido)-pentanedioic acid ([125I]8) in 65−80% (nondecay-corrected), 30−35% (decay corrected), and 59−75% (nondecay-corrected) radiochemical yields. Compound [125I]3 demonstrated 8.8 ± 4.7% injected dose per gram (%ID/g) within PSMA+ PC-3 PIP tumor at 30 min postinjection, which persisted, with clear delineation of the tumor by SPECT. Similar tumor uptake values at early time points were demonstrated for [18F]6 (using PET) and [125I]8. Because of the many radiohalogenated moieties that can be attached via the ε amino group, the intermediate Lys-C(O)-Glu is an attractive template upon which to develop new imaging agents for prostate cancer.