2-(3-{1-Carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-p entanedioic acid

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Shan L

2-(3-{1-Carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-p entanedioic acid

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Abstract

2-(3-{1-Carboxy-5-[(6-[(18)F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-p entanedioic acid, abbreviated as [(18)F]DCFPyL, was synthesized by Chen et al. for use in positron emission tomography of tumors expressing prostate-specific membrane antigen (PSMA) (1). PSMA is a type II transmembrane glycoprotein with three structural domains, including a 19-amino-acid intracellular domain, a 24-amino-acid transmembrane domain, and a large 707-amino-acid extracellular domain (2, 3). Two site-specific carboxypeptidase activities have been assigned to PSMA: N-acetylated alpha-linked acidic dipeptidase, which hydrolyzes the neuropeptide N-acetyl-aspartyl-glutamate (NAAG) in the brain to regulate release of neurotransmitters, and folate hydrolase activity, which is characterized by the cleavage of terminal glutamates from poly- and gamma-glutamated folates, which play a role in the cellular uptake of dietary folate (2). PSMA has been found to be expressed in the prostate at a level 1,000-fold greater than in other tissues, and many folds higher in prostate cancer tumors than in normal and benign prostate tissues (4, 5). High-grade hormone-sensitive and hormone-insensitive tumors have the greatest PSMA expression. PSMA is also consistently and abundantly expressed on the neovascular endothelium in a wide variety of human solid tumors, but not in blood vessels in normal tissues. These features of PSMA make it an optimal target for developing imaging and therapy strategies for prostate cancer (6). Besides antibodies and antibody fragments, low molecular weight compounds have also been intensively tested as PSMA inhibitors and as PSMA-targeted imaging agents (1, 6). These compounds can be largely classified into two types: ureas and phosphoramidates (1). Both types of compounds possess a terminal glutamate at the P1' position, which enables productive binding with PSMA. They are also amenable to modification with bulky substituents that interact with the arginine patch or tunnel region on PSMA. Investigators have synthesized a series of ureas, including [(18)F]DCFBC, [(18)F]DCFPyL, and [(111)In]3 (1, 7, 8). [(111)In]3 is a bivalent compound that was synthesized by incorporating a PSMA-binding Lys-Glu urea motif for exploiting click chemistry and a second lysine residue for subsequent modification with an imaging or therapeutic moiety (8). Studies have shown that these radiolabeled PSMA inhibitors have desirable properties as imaging agents for prostate cancer imaging in animal models (1, 7, 8). This chapter summarizes the data obtained with [(18)F]DCFPyL. In another chapter, the data obtained with [(111)In]3 are summarized. The data obtained with [(18)F]DCFBC can be reviewed in the chapter on [(18)F]DCFBC in MICAD.

DrugBank Data that Cites this Article

Drugs

Piflufolastat F 18

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Piflufolastat F 18	Glutamate carboxypeptidase 2	Protein	Humans	Yes	Binder	Details