Brain Tumor Res Treat 2018;6(2):47-53 / pISSN 2288-2405 / eISSN 2288-2413

REVIEW ARTICLE https://doi.org/10.14791/btrt.2018.6.e13

Current Radiopharmaceuticals for Positron Emission Tomography

of Brain Tumors
Ji-hoon Jung, Byeong-Cheol Ahn
Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Korea

Brain tumors represent a diverse spectrum of histology, biology, prognosis, and treatment options. Al-
though MRI remains the gold standard for morphological tumor characterization, positron emission to-
mography (PET) can play a critical role in evaluating disease status. This article focuses on the use of
PET with radiolabeled glucose and amino acid analogs to aid in the diagnosis of tumors and differen-
tiate between recurrent tumors and radiation necrosis. The most widely used tracer is 18F-fluorodeox-
yglucose (FDG). Although the intensity of FDG uptake is clearly associated with tumor grade, the ex-
act role of FDG PET imaging remains debatable. Additionally, high uptake of FDG in normal grey
matter limits its use in some low-grade tumors that may not be visualized. Because of their potential
to overcome the limitation of FDG PET of brain tumors, 11C-methionine and 18F-3,4-dihydroxyphenyl-
Received July 17, 2018 alanine (FDOPA) have been proposed. Low accumulation of amino acid tracers in normal brains allows
Revised September 17, 2018 the detection of low-grade gliomas and facilitates more precise tumor delineation. These amino acid
Accepted September 19, 2018 tracers have higher sensitivity and specificity for detecting brain tumors and differentiating recurrent
Correspondence tumors from post-therapeutic changes. FDG and amino acid tracers may be complementary, and
Byeong-Cheol Ahn both may be required for assessment of an individual patient. Additional tracers for brain tumor imag-
Department of Nuclear Medicine, ing are currently under development. Combinations of different tracers might provide more in-depth
School of Medicine, information about tumor characteristics, and current limitations may thus be overcome in the near fu-
Kyungpook National University,
ture. PET with various tracers including FDG, 11C-methionine, and FDOPA has improved the manage-
Kyungpook National University Hospital,
ment of patients with brain tumors. To evaluate the exact value of PET, however, additional prospec-
130 Dongdeok-ro, Jung-gu,
Daegu 41944, Korea tive large sample studies are needed.
Tel: +82-53-420-5583
Fax: +82-53-422-0864 Key Words 
Brain tumors; Positron emission tomography-computed tomography;
E-mail: [email protected] 18
F-FDG; C-11 methionine; 18F-FDOPA.

INTRODUCTION nization classifications also provide histologic grades based on

cellular alterations related to cancer aggressiveness. Grades I
Brain tumors can originate from different cells both from and II are considered low-grade tumors that have a prolonged
within the brain and from systemic tumors that have metasta- clinical course. Grade III and IV tumors are considered high-
sized to the brain. Primary brain tumors most commonly arise grade lesions rapidly leading to death when left untreated [3].
from glial cells [1]. With an annual age-adjusted incidence rate Despite multimodal treatment strategies, the prognosis for
of 28 per 100,000 in adults, gliomas account for approximate- patients with glioma is poor. The median survival for patients
ly 27.2% of all brain and other central nervous system tumors, varies according to tumor grade, location, and age at diagno-
and approximately 81.3% of all malignant tumors [2]. sis. Therefore, adequate tumor diagnosis and grading is thus
Gliomas can be categorized into different pathologic sub- crucial to initiate appropriate treatment and improve long-term
types. In addition to the pathologic type, World Health Orga- outcomes [4].
MRI with gadolinium contrast enhancement is the gold
This is an Open Access article distributed under the terms of the Creative Commons
Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) standard imaging modality for assessing the morphological
which permits unrestricted non-commercial use, distribution, and reproduction in any characteristics of brain tumors, such as location, mass effect,
medium, provided the original work is properly cited.
Copyright © 2018 The Korean Brain Tumor Society, The Korean Society for Neuro- and contrast enhancement; however, it has several limitations.
Oncology, and The Korean Society for Pediatric Neuro-Oncology It cannot always distinguish gliomas from non-neoplastic le-

47
PET Imaging for Brain Tumors

sions such as those resulting from vascular processes or in- lignancies elsewhere in the body, malignant brain tumors gen-
flammatory reactions. Because the absence of contrast en- erally have increased glucose metabolism and increased FDG
hancement does not always correspond to low-grade tumors, uptake, and FDG is actively transported across the intact blood-
MRI is not perfect for grading gliomas. Furthermore, distin- brain barrier (BBB) (Fig. 1). Anaerobic glycolysis has been shown
guishing tumor recurrence from post-surgical or post-radio- to occur in advanced cancers, even with an abundance of oxy-
therapeutic changes remains a major challenge in brain imaging gen, a process named the Warburg effect. The high glycolytic
studies [5]. In recent decades, molecular imaging with positron rate of cancerous lesions results from various biological chang-
emission tomography (PET) has gained increasing impor- es, including high levels of the membrane glucose transporter
tance in identifying and delineating areas of increased tumor and increased cytosolic glycolytic enzymes such as hexokinase.
growth activity. Various PET tracers have been developed to Consequently, the greater demand for glycolytic substrates
visualize tumors using the hallmarks of cancers, such as meta- causes increased transport of the glucose analog FDG into ma-
bolic derangement and replicative immortality. The tracer lignant cells [10-12].
18
F-fluorodeoxyglucose (FDG) visualizes glucose metabolism, FDG PET can be used to identify differences in glucose up-
radiolabeled amino acids [e.g., 11C-methionine, 18F-3,4-dihy- take among healthy brains, low- and high-grade gliomas, and
droxyphenylalanine (FDOPA), and O-(2-18F-Fluoroethyl)-l- radionecrosis [13,14]. FDG uptake is generally considered to
Tyrosine (FET)] perform protein synthesis, and 18F-fluorothy- reflect both tumor cell viability and density, and is directly re-
midine (FLT) performs DNA replications. PET fused with lated to tumor grade [15,16]. FDG uptake in low-grade tumors
computed tomography (PET/CT) can obtain detailed ana- is similar to that of white matter, whereas Grade III and IV
tomical information on PET results and provides clinically tumors exhibit glucose metabolic activity comparable to or
invaluable information regarding primary detection and dif- higher than that of grey matter (Fig. 2). A meta-analysis con-
ferentiation between various underlying tumor types, initial ducted by Zhao et al. [17] revealed that FDG PET was able to
tumor grading and risk stratification, therapy planning, selec- detect brain tumors with a sensitivity of 71% and a specificity
tion of biopsy site, response evaluation, and recurrence detec- of 77%, whereas another study on detecting high-grade glio-
tion [6-8]. The current article discusses some of the positive as- mas found that FDG PET had a sensitivity of 94% and a spec-
pects of the contemporary use of PET or PET/CT in primary ificity of 77% [9]. Because the similarities in glucose metabolic
brain tumors. activity between tumors and grey matter cause difficulties in
the analysis of FDG-PET images, several studies have shown
FDG PET that delaying scanning times by 3 hours after FDG injection
considerably improves the contrast between malignant brain
FDG PET imaging was first used to detect and differentiate tumors and normal brain tissue [18,19].
between low- and high-grade tumors [9]. Similar to most ma- Because treatment-induced changes such as radionecrosis

A B C
Fig. 1. FDG PET/MR for CNS lymphoma. 79-year-old woman diagnosed as CNS lymphoma. T2 fluid attenuated inversion recovery MRI
shows multiple lesions with high signal in both hemisphere (A). FDG PET (B) and FDG PET/MR (C) show intense tracer uptake at the le-
sions. FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography; CNS, central nervous system.

48 Brain Tumor Res Treat 2018;6(2):47-53

 JH Jung et al.

and post-surgical changes are highly difficult to distinguish evolving domain, promising higher sensitivity as well as high-
from tumor recurrence, evaluation of disease status after treat- er specificity for certain tumor entities [30]. Because of physi-
ment is challenging with MRI alone [20]. Conversely, FDG ologically low uptake in healthy brain tissue and absent or low
PET can detect recurrent high-grade tumors. Chao et al. [14] uptake in inflammatory lesions, radiolabeled amino acids or
reported sensitivity of 75% and specificity of 81% for FDG their analogs have been demonstrated to overcome the limita-
PET in differentiating recurrent tumors from post-radiation tions of FDG [31,32] .
changes. They also observed an improvement in the sensitivity
of tumor recurrence detection after stereotactic radiotherapy, Amino acid PET
from 65% to 85%, when FDG PET was added to standard
MRI. Previous studies have reported high sensitivities and Because of the limitations of FDG PET in assessing brain
specificities for FDG PET of 81–86% and 40–94%, respective- tumors, amino acid-based radiotracers have been developed.
ly, for distinguishing radionecrosis from residual or recurrent The most popular amino acid tracer is 11C-methionine, which
tumors whereas those for contrast enhanced MRI were 95% has been investigated in many studies on brain tumors (Fig. 3).
and 23%, respectively [21,22]. The use of 11C-methionine provides a high detection rate for
Wang et al. [23] defined the criteria for positive and nega- brain tumors and good lesion delineation because of the low
tive FDG PET scans as tracer uptake above or below the ex- physiological uptake of the amino acid in healthy brains with
pected uptake in the adjacent brain tissue, which achieved high high contrast between normal and cancerous tissue [33-38].
overall sensitivity and accuracy of 80% and 87%, respectively, Increased 11C-methionine uptake is associated with upregula-
with regard to differentiating recurrent tumors from post-ra- tion of L-type amino acid transporter 1 (LAT1) and prolifera-
diation changes. tion of the tumor microvasculature [39-42]. Although methio-
However, values of FDG PET are inherently limited by the nine PET has been shown to have high sensitivity for gliomas,
FDG avidity of normal brain tissue. The physiologic glucose false-positive results may be seen under benign conditions, such
consumption in the normal brain generates a high background as cases of demyelination, leukoencephalitis, or abscess [43].
uptake of FDG, which is generally high in gray matter, and Several studies diagnosing untreated brain tumors with me-
moderate to high in white matter [24-26]. In addition, various thionine PET have reported relatively high sensitivities, rang-
non-malignant intracerebral lesions also have varying levels ing from 76% to 91%, and specificities ranging from 75% to
of increased FDG uptake (e.g., with inflammatory or infec- 100% [35,38,44-47]. A recent meta-analysis found a 91% sen-
tious causes), and this also applies to normal brain tissue adja- sitivity and an 86% specificity [17]. Methionine PET is more
cent to tumor lesions. Thus, differentiating between malignant suitable than FDG PET alone for diagnosing and managing
and non-malignant causes of increased FDG uptake is difficult patients, particularly those with low-grade tumors [38,48,49].
[27-29]. In high-grade gliomas, tracer leakage from a disrupted BBB
Although FDG remains the most widely used radiotracer contributes considerably to amino acid uptake. However, in
for PET imaging, radiopharmaceutical development is an low-grade gliomas, amino acid uptake occurs without sub-

A B C
Fig. 2. FDG PET/MR for high-grade glioma. 18-year-old woman diagnosed as a glioblastoma, WHO grade IV. T2 fluid attenuated inversion
recovery MRI shows high signal in pontine lesion (A). FDG PET (B) and FDG PET/MR (C) show increased tracer uptake at the lesion (ar-
rows). FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography.

49
PET Imaging for Brain Tumors

stantial BBB breakdown, corresponding to an upregulation of fore, amino acid PET can be useful for treatment planning,
LAT1 [45]. Therefore, the relationship between tumor grade and Grosu et al. [67] reported better outcomes for patients
and the intensity of amino acid analog uptake remains subject to with radiotherapy planned on the basis of tumor extent as de-
speculation; some studies have reported strong correlation be- fined using amino acid PET.
tween the two parameters [50-52], whereas others have reached FDOPA PET provides crucial information for the detection
the opposite conclusion [53-55]. of recurrent brain tumors as well as initial diagnosis. It is a
Methionine PET can also detect recurrent tumors with high valuable tool for treatment monitoring because it helps in as-
sensitivity and specificity, allowing differentiation between tu- sessing treatment response and evaluating patient prognosis
mor recurrence and radionecrosis. A recent meta-analysis of after therapy. Previous studies have reported sensitivity and
methionine PET reported a summary sensitivity of 70% and specificity of FDOPA PET for detecting tumor recurrence as
specificity of 93% for high-grade gliomas in the detection of ranging from 90% to 92% and from 92% to 95%, respectively
recurrent tumors [56]. [32,68,69].
However, because of the short half-life of 11C, 18F-labeled
amino acid tracers were developed, such as FDOPA and FET FLT PET
[4,31,57,58]. Whereas FDOPA is widely spread in the United
States, FET is more common in Europe [59]. The pyrimidine analog 3’-deoxy-3’-FLT has been studied as
Similar to radiolabeled methionine, uptake of FDOPA is a marker of tumor proliferation rate by reflecting thymidine
mediated by amino acid transporters and does not require dis- kinase-1 activity, which is the principle enzyme in the path-
ruption of the BBB. Therefore, FDOPA and 11C–methionine way of DNA synthesis. Because no transporter has sufficient
have similar distribution in tumors [60,61]. capacity, uptake of FLT in the brain depends on BBB permea-
Despite published series having involved mixed patients bility. In brain tumors with a damaged BBB, therefore, FLT pro-
populations, FDOPA PET reportedly has high sensitivity and vides highly reliable tumor-to-background contrast but cannot
specificity for detecting brain tumors, ranging from 85% to be used in low-grade gliomas with an intact BBB [70,71].
100% and from 86% to 90%, respectively [60,62-64]. Accumu- Whereas the sensitivity of FLT PET for detecting high-grade
lation of FDOPA does not vary substantially within different gliomas can reach 100%, a lower overall sensitivity of 83% has
tumor grades, and the amino acid analog is clearly superior to been shown because of major differences in uptake between
18
F-FDG for diagnosing low- and high-grade gliomas [64,65]. high- and low-grade tumors [72,73]. Hence, the sensitivity of
Because FDOPA uptake in brain tumors does not depend all grades is typically lower than with FDG PET [74] and me-
on the BBB, delineation of tumor extent is reportedly more ac- thionine PET [75]. Conversely, FLT PET seems to be superior
curate, and areas with increased uptake on PET are often larger to methionine PET in tumor grading and assessment of pro-
than areas with contrast-enhanced lesions on MRI [66]. There- liferation activity in gliomas of different grades [76,77].

A B C
Fig. 3. 11C-methionine PET/MR. 5-year-old girl diagnosed low-grade glioma in cerebellum. T2 fluid attenuated inversion recovery MRI shows
high signal in a cerebellar lesion (A). 11C-methionine PET (B) and 11C-methionine PET/MR (C) show increased tracer uptake at the cerebellar
lesion. PET, positron emission tomography.

50 Brain Tumor Res Treat 2018;6(2):47-53

 JH Jung et al.

Future perspectives ous biological statuses of brain tumors and improves diagnos-
tic and therapeutic planning in certain patients with brain tu-
Because the information gained by different imaging meth- mors. Advancement of PET chemistry and development of
ods is complementary and brain PET scans generally should imaging technologies will broaden the applications of PET
not be interpreted without access to the corresponding MRI imaging in the field of brain tumors.
scans, combining all imaging methods might provide optimal
results for assessment of tumor characteristics [78-83]. Com- Conflicts of Interest
The authors have no financial conflicts of interest.
bined PET/MR can readily be achieved using standard soft-
ware and is provided more directly and conveniently by hy- Acknowledgments
brid PET/MR machines (Fig. 1-3). Although the effect of image This work was supported by a National Research Foundation of Korea
fusion does not play an essential role in the case of brain imag- (NRF) grant funded by the South Korea government (2014R1A5A2009
242).
ing, accurate image fusion can be easily obtained through im- The authors would like to thank professor Jin Chul Paeng (Seoul Na-
age co-registration based on fixed points. PET/MR also has tional University Hospital, Seoul, Korea) for providing PET/MR images.
the advantage of low radiation exposure compared to PET/
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