Prostate-specific membrane antigen (PSMA, GCPII)

Prostate-specific membrane antigen is a type II transmembrane glycoprotein with zinc-depending enzymatic functions. Because of its different roles it is also known as glutamate carboxypeptidase II (GCPII), N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I), NAAG peptidase, and folate hydrolase 1 (FOLH1). It is encoded by the FOLH1 gene. The protein (in humans) has a 707-amino-acid extracellular portion, 24-amino-acid transmembrane portion, and 19-amino-acid intracellular portion. PSMA is highly glycosylated with oligosaccharides, which are essential for proper protein folding and enzymatic activity (Mesters et al., 2006). PSMA shares homology with the transferrin receptor. The enzymatic functions of PSMA can be inhibited with specific antibodies or small molecule inhibitors; after binding, these are internalized with PSMA by endocytosis (Ghosh and Heston, 2004; Eder et al., 2013).

Prostate-specific membrane antigen is expressed in prostate tissue (epithelium), salivary glands, tubular cells in the kidneys, intestine (especially proximal small intestine), and in the central and peripheral nervous system. In prostate tumours, their metastases, and in neovasculature the PSMA is highly overexpressed, providing a target for imaging and therapy (Sweat et al, 2008; Mannweiler et al., 2009; Haberkorn et al., 2016; Baum et al., 2016; Eiber et al., 2017; Ahn et al., 2019). Only 5-10% of primary prostate cancer lesions are PSMA-negative (Schwarzenboeck et al., 2017). PSMA expression in neovascular endothelium (also in other than prostate tumours) may be related to cell invasion and angiogenesis (Conway et al., 2006). PSMA is expressed in neovasculature of non-cancerous tissues, too, which may lead to uptake of PSMA radioligands for instance in sites of bone remodeling (Artigas et al., 2016).

PSMA hydrolyses carboxy-terminal glutamate residues (thus the name GCPII); this activity manifests as folate hydrolase in the small intestine (in duodenal brush border cells), freeing folic acid to be used in the body as a vitamin. Mutation of FOLH1 gene may lead to impaired intestinal absorption of folate. PSMA may also play a role in the folate metabolism of the prostate (Pinto et al., 1996; Heston, 1997; Chang, 2004). In kidneys PSMA may participate in folate reabsorption.

In the brain, neuropeptide N-acetyl-L-aspartyl-L-glutamate is a substrate of glutamate carboxypeptidase; PSMA expression may be involved with glutamate excitotoxicity (Bařinka et al., 2012).

Matrix metalloproteinase-2 (MMP-2) and PSMA can participate in a proteolytic pathway in extracellular matrix generating small, pro-angiogenic laminin peptides, which enhance endothelial cell adhesion and migration, and activate adhesion via integrins, leading to increased angiogenesis (Conway et al., 2006 and 2013).

PET tracers for PSMA

Monoclonal antibodies

Monoclonal antibodies, conjugated with DOTA and labelled with 64Cu, have shown promise in PSMA-positive tumour model in mice (Elsässer-Beile et al., 2009; Alt et al., 2010; Fung et al., 2016). Banerjee et al (2014) compared different chelators and found that CB-TE2A provided better contrast than NOTA, PCTA, Oxo-DO3A or DOTA, probably due to its higher stability. Intact antibodies usually have poor tumour penetration and slow blood-pool clearance, as demonstrated by the SPECT tracer [111In]capromab pendetide.

Development of specific and strongly binding monoclonal antibodies to PSMA is difficult because of the high glycosylation of native PSMA. Capromab pendetide and some other mAbs bind to the portion of PSMA that is not exposed on the outer cell surface, such as 7E11, and thus cannot be used to target viable cells. J591 binds the extracellular domain of PSMA, and has been labelled with 89Zr and 124I for PET imaging and also used in radioimmunotherapy.

Because of the limitations of mAbs, small-molecule PSMA ligands have become the object of interest. Anti-PSMA affibodies may be better suited for tumour imaging (Chatalic et al., 2015).

Urea-based radioligands

Several urea-based PSMA inhibitors, with low molecular weight, have been developed to be used as SPECT and PET radiopharmaceuticals (Eder et al., 2012, Foss et al., 2012). Many of the proposed PSMA ligands contain a chelator, which can bind a variety of radioisotopes. While 18F and 68Ga are most often used, radioisotopes with longer half-lives, such as 64Cu, 89Zr, and 55Co, have been used for delayed imaging.

One of most used PET tracers for imaging PSMA expressing tumours is [68Ga]PSMA-HBED-CC ([68Ga]PSMA-11). This tracer binds to the extracellular domain of PSMA and is then assumed to be internalized. Image contrast is better than with [18F]fluoromethylcholine (Afshar-Oromieh et al., 2014). It is used for initial staging and detecting recurrent prostate cancer (Bailey & Piert, 2017).

[18F]DCFBC has potential for detection of metastatic prostate cancer (Cho et al., 2012). Blood clearance is relatively slow, partly due to binding to the circulating form of PSMA. Tracer is mainly excreted via kidneys, leading to high radioactivity concentration in the bladder. The fraction of radioactive metabolites in plasma is very low (Cho et al., 2012).

[18F]DCFPyl (Chen et al., 2011) has lower blood activity and better sensitivity than [18F]DCFBC and [68Ga]PSMA-HBED-CC (Mena et al., 2018; Dietlein et al., 2017; Kesch et al., 2017).

[18F]PSMA-1007 has shown comparable performance to [68Ga]PSMA-HBED-CC, with reduced urinary excretion (Dietlein et al., 2017; Giesel et al., 2017; Kesch et al., 2017). Good tumour-to-background ratios in primary and recurring prostate cancer can be observed 2-3 h after administration (Giesel et al., 2017 and 2018). Visual analysis of images obtained ∼90 min after administration provided high detection rates for biochemical recurrence of prostate cancer (Giesel et al., 2019).

With [18F]PSMA-7, at least equal performance to [68Ga]PSMA-HBED-CC has been obtained 3 h after administration (Dietlein et al., 2018; Hohberg et al., 2018).

Phosphonate-based radioligands

Phosphonates and phosphoramidates have been used as PSMA inhibitors, and labelled for PSMA imaging. PET radioligands of this group includes for instance (2RS,4S)-2-[18F]fluoro-4-phosphonomethyl-pentanedioic acid ([18F]BAY1075553) (Lesche et al., 2014; Beheshti et al., 2015), and [18F]CTT1057 (Behr et al., 2019).

For radiotherapy, long circulation times and low excretion into urine are preferred. Adding an albumin-binding moiety to the PSMA ligands can be used optimize the tissue distribution profile, while still enabling internalization into PSMA overexpressing cancer cells (Benešová et al., 2018).

See also:


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Chang SS. Overview of prostate-specific membrane antigen. Rev Urol. 2004; 6: S13-S16. PMID: 16985927.

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Foss CA, Mease RC, Cho SY, Kim HJ, Pomper MG. GCPII imaging and cancer. Curr Med Chem. 2012; 19: 1346-1359. doi: 10.2174/092986712799462612.

Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem. 2004; 91(3): 528-539. doi: 10.1002/jcb.10661.

Heston WDW. Characterization and glutamyl preferring carboxypeptidase function of prostate specific membrane antigen: a novel folate hydrolase. Urology 1997; 49(3A): 104-112. doi: 10.1016/S0090-4295(97)00177-5.

Malaspina S, De Giorgi U, Kemppainen J, Del Sole A, Paganelli G. 68Ga-PSMA-PET: added value and future applications in comparison to the current use of choline-PET and mpMRI in the workup of prostate cancer. Radiol Med. 2018; (in press). doi: 10.1007/s11547-018-0929-9.

Mesters JR, Barinka C, Li W, Tsukamoto T, Majer P, Slusher BS, Konvalinka J, Hilgenfeld R. Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer. EMBO J. 2006; 25(6): 1375-1384. doi: 10.1038/sj.emboj.7600969.

Rojas C, Frazier ST, Flanary J, Slusher BS. Kinetics and inhibition of glutamate carboxypeptidase II using a microplate assay. Anal Biochem. 2002; 310: 50-54. doi: 10.1016/S0003-2697(02)00286-5.

Tewari A (ed.): Prostate Cancer: A Comprehensive Perspective. Springer, 2013. ISBN 978-1-4471-2863-2. doi: 10.1007/978-1-4471-2864-9.

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Updated at: 2019-12-05
Created at: 2015-03-25
Written by: Vesa Oikonen, Anne Roivainen