Cancer Imaging With Fluorine-18–Labeled Choline Derivatives

doi:10.1053/j.semnuclmed.2007.07.003

Seminars in Nuclear Medicine

Volume 37, Issue 6, November 2007, Pages 420-428

https://doi.org/10.1053/j.semnuclmed.2007.07.003 Get rights and content

The choline transporter and choline kinase enzyme frequently are overexpressed in malignancy. Therefore, positron-emitter-labeled compounds derived from choline have the potential to serve as oncologic probes for positron emission tomography. The fluorine-18 (¹⁸F)–labeled choline derivative fluorocholine (FCH) in particular has demonstrated potential utility for imaging of a variety of neoplasms, including those of the breast, prostate, liver, and brain. The pharmacokinetics of FCH and other choline tracers allow for whole-body imaging within minutes of injection while still achieving high tumor-to-background contrast in most organs, including the brain. These features, along with the possibility of imaging malignancies that have proved elusive with the use of ¹⁸F-fluorodeoxyglucose positron emission tomography support further clinical investigations of ¹⁸F-labeled choline tracers.

Section snippets

Development of Choline Tracers Labeled With Fluorine-18

Tumor imaging with choline-based tracers was introduced by Hara and coworkers using carbon-11 (¹¹C) choline PET to successfully visualize brain tumors and prostate cancer.4, 5 As a true tracer, ¹¹C choline is biochemically indistinguishable from natural choline. This compound has shown particular promise for imaging tumors of the genitourinary tract because of its limited urinary clearance and avidity for bladder and prostate cancers.6, 7, 8, 9, 10, 11 However, the short decay half-life of the

Prostate Cancer Imaging With Fluorocholine

Prostate cancer is the second-leading cause of cancer death in American men older than 50 years of age. Clinically, there has been a long-standing need for better imaging methods that can be applied to diagnose, risk stratify, stage, and direct treatments for prostate cancer. Conventional ¹⁸F-fluorodeoxyglucose (FDG)-PET has proven to be of limited usefulness for diagnosing prostate cancer, although it does appear possible to detect advanced or metastatic prostate cancer with this technique.29,

Brain Imaging

DeGrado and coworkers first reported brain tumor imaging with ¹⁸F-FCH in a patient with biopsy proven recurrent anaplastic astrocytoma.¹⁸ These investigators noted that the low concentration of FCH in normal cerebral cortex allowed for excellent delineation of the tumor from normal brain. They observed that a ∼10:1 tumor-to-cortex ratio was achievable within 5-minutes of tracer injection. FDG-PET revealed a corresponding area of increased FDG uptake; however, the tumor boundaries were difficult

Liver Imaging

Hepatocellular carcinoma (HCC) is the fifth most frequent cancer worldwide and the most frequent cause of death in cirrhotic patients.¹ The sensitivity of FDG-PET for the detection of HCC is suboptimal, ranging between 50% and 70%.3, 4 Given that the use of MRS demonstrates high choline content in HCC, it may be possible to detect this disease using FCH,⁷ despite the fact that the liver demonstrates significant physiologic uptake of FCH. A proof of concept study was performed by Talbot and

Practical Issues and Potential Pitfalls in FCH-PET Imaging

FCH is effectively cleared from the blood within minutes after its intravenous administration. During this brief period of rapid clearance, FCH is capable of significant uptake and retention by malignant tumors, while achieving minimal retention in organs such as the heart and brain. These features of FCH are advantageous, because they allow for very efficient scanning of the entire body. However, as a consequence of rapid blood clearance, the tissue distribution of FCH is likely to be

Conclusion

The ¹⁸F-labeled choline analogs, and in particular FCH, are currently under investigation as oncologic probes for the detection and monitoring of malignancies. These probes may be viewed as in vivo biomarkers of choline transporter and CK activity, although their uptake may also reflect a component of tissue perfusion. To date, the majority of studies have focused on the use of the FCH PET to evaluate prostate cancer, with preliminary studies having provided encouraging results for detecting

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Oncology, bone metastases
2022, Nuclear Medicine and Molecular Imaging: Volume 1-4
Metastatic disease is the most common malignancy of the bone and the skeleton is one of the preferential sites for metastases of solid tumor. Osteotropic radiopharmaceuticals are bone seeking agents which target skeleton due to their osteoblastic activity. The most common in clinical use is Sodium-18 fluoride (Na¹⁸F).
¹⁸F-NaF PET/CT plays essential role in initial staging, detection of suspected metastases, suspected progression of osseous metastases or treatment monitoring in many types of cancer, such as prostate, breast and lung cancer. Additionally, the role¹⁸F-NaF PET/CT in the diagnostics of thyroid cancer, renal cell cancer, multiple myeloma and metastatic primary bone tumors is discussed.
Specific oncotropic PET agents are tumor targeting compounds, such as Iodine-124 for metastatic thyroid cancer, and somatostatin analogs (Ga-⁶⁸DOTA-octreotide/octreotate) for neuroendocrine neoplasms. These tracers disclose bone metastases in the malignancies. Multiple tracers for prostate cancer are presented with varying ability to target malignant skeletal disease. Hormone receptor imaging is presented, FES PET is a prime example to demonstrate estrogen receptor positive skeletal disease.
Non-specific oncotropic Agents are important in the detection of skeletal metastases. Actually, the most common PET tracer, F-18 fluorodeoxyglucose (¹⁸F-FDG), plays an important role in the diagnosis of many malignancies. However, the differential diagnosis and sensitivity may sometimes cause problems which should be identified. F-18 (C-11) Choline is associated with lipid synthesis and more sensitive than conventional bone scintigraphy in the diagnosis of bone metastases of prostate cancer. On the contrary, fluorothymidine (¹⁸F-FLT) which targets DNA and cellular proliferation, is not sensitive at all the in the follow-up of skeletal metastases.
This article provides an overview about the diagnostics of bone metastases. Additionally, practical pitfalls are presented as well as new ideas how to improve diagnostics, such as quantitation methods and double-tracer techniques.
Hepatocellular Carcinomas With Mutational Activation of Beta-Catenin Require Choline and Can Be Detected by Positron Emission Tomography
2019, Gastroenterology
In one-third of hepatocellular carcinomas (HCCs), cancer cells have mutations that activate β-catenin pathway. These cells have alterations in glutamine, bile, and lipid metabolism. We investigated whether positron emission tomography (PET) imaging allows identification of altered metabolic pathways that might be targeted therapeutically.
We studied mice with activation of β-catenin in liver (Apc^ko-liv mice) and male C57Bl/6 mice given injections of diethylnitrosamine, which each develop HCCs. Mice were fed a conventional or a methionine- and choline-deficient diet or a choline-deficient (CD) diet. Choline uptake and metabolism in HCCs were analyzed by micro-PET imaging of mice; livers were collected and analyzed by histologic, metabolomic, messenger RNA quantification, and RNA-sequencing analyses. Fifty-two patients with HCC underwent PET imaging with ¹⁸F-fluorodeoxyglucose, followed by ¹⁸F-fluorocholine tracer metabolites. Human HCC specimens were analyzed by immunohistochemistry, quantitative polymerase chain reaction, and DNA sequencing. We used hepatocytes and mouse tumor explants for studies of incorporation of radiolabeled choline into phospholipids and its contribution to DNA methylation. We analyzed HCC progression in mice fed a CD diet.
Livers and tumors from Apc^ko-liv mice had increased uptake of dietary choline, which contributes to phospholipid formation and DNA methylation in hepatocytes. In patients and in mice, HCCs with activated β-catenin were positive in ¹⁸F-fluorocholine PET, but not ¹⁸F-fluorodeoxyglucose PET, and they overexpressed the choline transporter organic cation transporter 3. The HCC cells from Apc^ko-liv mice incorporated radiolabeled methyl groups of choline into phospholipids and DNA. In Apc^ko-liv mice, the methionine- and choline-deficient diet reduced proliferation and DNA hypermethylation of hepatocytes and HCC cells, and the CD diet reduced long-term progression of tumors.
In mice and humans, HCCs with mutations that activate β-catenin are characterized by increased uptake of a fluorocholine tracer, but not ¹⁸F-fluorodeoxyglucose, revealed by PET. The increased uptake of choline by HCCs promotes phospholipid formation, DNA hypermethylation, and hepatocyte proliferation. In mice, the CD diet reverses these effects and promotes regression of HCCs that overexpress β-catenin.
Comparison of [18F]Fluorocholine and [18F]Fluordesoxyglucose for assessment of progression, lung metastasis detection and therapy response in murine 4T1 breast tumor model
2018, Applied Radiation and Isotopes
Citation Excerpt :
[18F]FCH is an analogue of choline, a precursor for the biosynthesis of cell membrane phospholipids, which form the bilayer structures of all cellular membranes, an essential component of all cells. The [18F]FCH uptake by mammary tumor may be due to higher choline kinase (CK) expression in these cells, similarly to what happens in prostate cancer cells (Kwee et al., 2007). Interestingly, studies have shown that breast cancer tissue displayed increased phospholipid content as compared to non-cancerous adjacent healthy breast tissue.
The [¹⁸F]Fluorocholine ([¹⁸F]FCH) tracer for PET imaging has been proven to be effective for several malignances. However, there are only a few studies related to its breast tumor applicability and they are still limited. The aim of this study was investigate the efficacy of [¹⁸F]FCH/PET compared to [¹⁸F]FDG/PET in a murine 4T1 mammary carcinoma model treated and nontreated. [¹⁸F]FCH/PET showed its applicability for primary tumor and lung metastasis detection and their use for response monitoring of breast cancer therapeutics at earlier stages.
Use of 68Ga-PSMA-11 PET/CT when 18F-fluorocholine cannot localize biological recurrence of prostate cancer: Report of a case and review of the literature
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L’augmentation de la concentration sérique de l’antigène spécifique de la prostate (PSA) est un problème croissant se produisant chez plus du tiers des patients qui ont bénéficié d’un geste radical pour la prise en charge initiale d’un cancer de la prostate. Chez ces patients, Il est donc très important d’identifier par imagerie les foyers de récidive avant de proposer un traitement loco-régional ou systémique. L’intérêt de la TEP/TDM à la ¹⁸F-fluorocholine (FCH) dans cette indication est démontré depuis plusieurs années. Récemment, des ligands de l’antigène transmembranaire PSMA, exprimé par pratiquement tous les cancers de la prostate, ont été marqués avec des nucléides pour l’imagerie TEP. La TEP/TDM au ⁶⁸Ga-PSMA-11 (PSMA-11) a été décrite comme supérieure à la FCH, mais aussi à l’imagerie conventionnelle, pour déceler la récidive de cancer de la prostate. Nous présentons ici le cas d’un patient avec un antécédent de prostatectomie pour cancer de prostate et posant le problème d’une élévation du PSA sans cible suspecte de maladie résiduelle ni avec la FCH, ni sur l’IRM pelvienne. Le PSMA-11 a identifié une cible ganglionnaire pelvienne et a permis d’entreprendre une thérapeutique curative ciblée et d’éviter la mise en route d’une hormonothérapie « palliative ». Nous présentons ensuite une courte revue de la littérature sur ce sujet, avec présentation des performances publiées de la TEP au PSMA-11 et des principaux pièges d’interprétation.
A rise in prostate-specific antigen serum level (PSA) is an increasing issue, which occurs in more than one third of the patients who underwent radical prostatectomy. Thus, imaging these patients is of importance in order to localize residual disease and then to propose suitable therapy. The usefulness of ¹⁸F-fluorocholine (FCH) PET/CT in this indication has been demonstrated for several years. Recently, specific ligands of the prostate-specific membrane antigen (PSMA), which is expressed by almost all prostate cancers, were labelled with PET radionuclides. ⁶⁸Ga-PSMA-11 (PSMA-11) PET/CT has been described as superior to FCH and conventional imaging to detect prostate cancer recurrence. We present the case of a patient with history of prostate cancer, treated by surgery, referred for a rise in PSA serum level and without any residual disease targeted neither on FCH, nor on pelvic MRI. The PSMA-11 PET/CT demonstrated a pelvic lymph node, which was suspect of recurrence and allowed to initiate a specific curative therapy, replacing the “palliative” hormonotherapy, which was planned. A short review of the literature on this topic, focusing on the published PSMA-11 performances and main known interpretation pitfalls.
PET/Computed Tomography Scanning and Precision Medicine: Esophageal Cancer
2017, PET Clinics
Metabolic targeting can improve the efficiency of brain tumor biopsies
2020, Seminars in Oncology
Brain tumors comprise a heterogeneous group of diseases, featuring different biology, prognosis, and treatment. The most known forms are malignant gliomas and metastases. Brain biopsy is a recognized technique in the management of intracranial space-occupying lesions and tumors in particular. Tumor heterogeneity of malignant brain lesions has been described and can lead to significant sampling errors in stereotactic biopsy. Different methods have been used to perform biopsies, including biopsy guided by CT or RMI, echoguided or stereotactic. The choice of the target with the help of PET and MRI with spectroscopy allows one to identify metabolically more active areas of the tumor, and in this way reduce the rate of negative results.

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: Supported by U.S. Department of Defense Prostate Cancer Research Program Grant PC04130, and National Institutes of Health/ National Cancer Institute grant CA108620.

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Cancer Imaging With Fluorine-18–Labeled Choline Derivatives

Section snippets

Development of Choline Tracers Labeled With Fluorine-18

Prostate Cancer Imaging With Fluorocholine

Brain Imaging

Liver Imaging

Practical Issues and Potential Pitfalls in FCH-PET Imaging

Conclusion

Biochem Biophys Res Commun

J Urol

Eur Urol

Appl Radiat Isot

J Clin Neurosci

Semin Nucl Med

J Urol

Urology

J Urol

J Urol

Semin Nucl Med

J Urol

Nucl Med Biol

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