PET Tracers Beyond FDG in Prostate Cancer

https://doi.org/10.1053/j.semnuclmed.2016.07.005Get rights and content

Conventional anatomical imaging with CT and MRI has limitations in the evaluation of prostate cancer. PET is a powerful imaging technique, which can be directed toward molecular targets as diverse as glucose metabolism, density of prostate-specific membrane antigen receptors, and skeletal osteoblastic activity. Although 2-deoxy-2-18F-FDG-PET is the mainstay of molecular imaging, FDG has limitations in typically indolent prostate cancer. Yet, there are many useful and emerging PET tracers beyond FDG, which provide added value. These include radiotracers interrogating prostate cancer via molecular mechanisms related to the biology of choline, acetate, amino acids, bombesin, and dihydrotestosterone, among others. Choline is used for cell membrane synthesis and its metabolism is upregulated in prostate cancer. 11C-choline and 18F-choline are in wide clinical use outside the United States, and they have proven most beneficial for detection of recurrent prostate cancer. 11C-acetate is an indirect biomarker of fatty acid synthesis, which is also upregulated in prostate cancer. Imaging of prostate cancer with 11C-acetate is overall similar to the choline radiotracers yet is not as widely used. Upregulation of amino acid transport in prostate cancer provides the biologic basis for amino acid–based radiotracers. Most recent progress has been made with the nonnatural alicyclic amino acid analogue radiotracer anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (FACBC or fluciclovine) also proven most useful for the detection of recurrent prostate cancer. Other emerging PET radiotracers for prostate cancer include the bombesin group directed to the gastrin-releasing peptide receptor, 16β-18F-fluoro-5α-dihydrotestosterone (FDHT) that binds to the androgen receptor, and those targeting the vasoactive intestinal polypeptide receptor 1 (VPAC-1) and urokinase plasminogen activator receptor (uPAR), which are also overexpressed in prostate cancer.

Section snippets

Choline

Choline is a substrate for the synthesis of phosphatidylcholine, which is the major phospholipid in the cell membrane. The uptake of choline is mediated by a specific transporter, upregulated along with choline kinase activity in tumor cells.1 The physiological uptake of 11C-choline includes salivary glands, liver, kidney parenchyma, and pancreas, with faint uptake in spleen, bone marrow, and muscles. Bowel and bladder activity can occasionally be observed. 11C has a half-life of 20 minutes, so

Acetate

Acetate is a naturally occurring fatty acid precursor that is converted to acetyl-CoA, a substrate for the tricarboxylic acid cycle. Acetyl-CoA is incorporated into cholesterol and fatty acids and therefore 11C-acetate uptake is an indirect biomarker of fatty acid synthesis. This property is exploited for tumor imaging with 11C-acetate.26 Thanks to its short half-life (20 minutes), 11C-acetate delivers a relatively low effective dose (0.0049 mSv/MBq) to the patient and is a suitable compound for

Amino Acid PET Including Fluciclovine

Another aspect of the metabolome of prostate cancer, which can be exploited for molecular imaging is that of amino acids, as amino acid transport and metabolism is upregulated in prostate and other cancers.47, 48, 49, 50 Many amino acid transporter systems are overexpressed in prostate cancer, particularly the system ASC transporter ASCT2 and the system L transporter LAT1, which have been associated with tumor aggressiveness and poor survival.51, 52, 53, 54, 55, 56, 57, 58, 59, 60 In addition,

Bombesin

Another target for prostate cancer molecular imaging that is under active investigation involves the gastrin-releasing peptide receptor (GRPR) that is reported to be overexpressed in prostate cancer with little to no activity in normal or hypertrophied prostate tissue.50 Bombesin analogues are shortened and more stable versions of the full 27–amino acid mammalian gastrin-releasing peptide, involved in multiple signaling pathways, but which has insufficient in vivo stability in itself to be the

18F-Fluorodihydrotestosterone

Androgens play an important role in the pathogenesis of prostate cancer, and overexpression of androgen receptors (ARs) occurs in all stages of the disease. Thus, a radiotracer that probes the molecular pathway of dihydrotesterone that is the primary ligand binding to the AR may serve a useful role in both clinical and research imaging of prostate cancer.

A PET radiotracer based on dihydrotesterone, 16β-18F-fluoro-5α-dihydrotestosterone (FDHT), which binds to sex hormone–binding globulin and

Other Emerging PET Radiotracers

Among other amino acid imaging, cationic system ATB0,+ transport with O-2((2-[18F]fluoroethyl)methyl-amino)ethyltyrosine ([18F]FEMAET) has been studied in prostate cancer PC-3 cells and mice xenografts.60 A system X−c PET radiotracer (4S)-4-(3-[18F]fluoropropyl)-l-glutamate ([18F]FSPG) has also been developed with good visualization of 5 of 10 patients with primary prostate cancer and 7of 10 patients with recurrent or metastatic disease.122 Finally,11C and 18F system A transport radiotracers

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