Update on the Use of PET/MRI Contrast Agents and Tracers in Brain Oncology: A Systematic Review

Abstract

The recent advancements in hybrid positron emission tomography–magnetic resonance imaging systems (PET/MRI) have brought massive value in the investigation of disease processes, in the development of novel treatments, in the monitoring of both therapy response and disease progression, and, not least, in the introduction of new multidisciplinary molecular imaging approaches. While offering potential advantages over PET/CT, the hybrid PET/MRI proved to improve both the image quality and lesion detectability. In particular, it showed to be an effective tool for the study of metabolic information about lesions and pathological conditions affecting the brain, from a better tumor characterization to the analysis of metabolic brain networks. Based on the PRISMA guidelines, this work presents a systematic review on PET/MRI in basic research and clinical differential diagnosis on brain oncology and neurodegenerative disorders. The analysis includes literature works and clinical case studies, with a specific focus on the use of PET tracers and MRI contrast agents, which are usually employed to perform hybrid PET/MRI studies of brain tumors. A systematic literature search for original diagnostic studies is performed using PubMed/MEDLINE, Scopus and Web of Science. Patients, study, and imaging characteristics were extracted from the selected articles. The analysis included acquired data pooling, heterogeneity testing, sensitivity analyses, used tracers, and reported patient outcomes. Our analysis shows that, while PET/MRI for the brain is a promising diagnostic method for early diagnosis, staging and recurrence in patients with brain diseases, a better definition of the role of tracers and imaging agents in both clinical and preclinical hybrid PET/MRI applications is needed and further efforts should be devoted to the standardization of the contrast imaging protocols, also considering the emerging agents and multimodal probes.

Full text

REVIEW
Update on the Use of PET/MRI Contrast Agents and
Tracers in Brain Oncology: A Systematic Review
Alessio Smeraldo
1–3,
*, Alfonso Maria Ponsiglione
1,
*, Andrea Soricelli
4
, Paolo Antonio Netti
1–3
,
Enza Torino
1–3
1
Department of Chemical, Materials and Production Engineering, University of Naples “Federico II”, Naples, 80125, Italy;
2
Interdisciplinary Research
Center on Biomaterials, CRIB, Naples, 80125, Italy;
3
Center for Advanced Biomaterials for Health Care, CABHC, Istituto Italiano di Tecnologia,
IIT@CRIB, Naples, 80125, Italy;
4
Department of Motor Sciences and Healthiness, University of Naples “Parthenope”, Naples, 80133, Italy
*These authors contributed equally to this work
Correspondence: Enza Torino, Department of Chemical, Materials and Production Engineering, University of Naples “Federico II”, Piazzale Tecchio
80, Naples, 80125, Italy, Tel +39-328-955-8158, Email enza.torino@unina.it
Abstract: The recent advancements in hybrid positron emission tomography–magnetic resonance imaging systems (PET/MRI) have
brought massive value in the investigation of disease processes, in the development of novel treatments, in the monitoring of both
therapy response and disease progression, and, not least, in the introduction of new multidisciplinary molecular imaging approaches.
While offering potential advantages over PET/CT, the hybrid PET/MRI proved to improve both the image quality and lesion
detectability. In particular, it showed to be an effective tool for the study of metabolic information about lesions and pathological
conditions affecting the brain, from a better tumor characterization to the analysis of metabolic brain networks. Based on the PRISMA
guidelines, this work presents a systematic review on PET/MRI in basic research and clinical differential diagnosis on brain oncology
and neurodegenerative disorders. The analysis includes literature works and clinical case studies, with a specic focus on the use of
PET tracers and MRI contrast agents, which are usually employed to perform hybrid PET/MRI studies of brain tumors. A systematic
literature search for original diagnostic studies is performed using PubMed/MEDLINE, Scopus and Web of Science. Patients, study,
and imaging characteristics were extracted from the selected articles. The analysis included acquired data pooling, heterogeneity
testing, sensitivity analyses, used tracers, and reported patient outcomes. Our analysis shows that, while PET/MRI for the brain is
a promising diagnostic method for early diagnosis, staging and recurrence in patients with brain diseases, a better denition of the role
of tracers and imaging agents in both clinical and preclinical hybrid PET/MRI applications is needed and further efforts should be
devoted to the standardization of the contrast imaging protocols, also considering the emerging agents and multimodal probes.
Keywords: PET/MRI, contrast agents, radiotracers, brain oncology, medical imaging
Introduction
At present, Magnetic Resonance Imaging (MRI) is the principal diagnostic modality for evaluating patients with brain
lesions to diagnose and localize brain tumors. It provides excellent soft-tissue characterization capabilities, comparatively
high resolution, and high availability.
1
However, on the downside, its specicity for neoplastic tissue is low, hampering
the evaluation of the grade of malignancy, tumor progression or potential growth of a lesion.
2
Furthermore, MRI can
present limitations in assessing treatment response after surgery, chemotherapy, and radiotherapy or in quantifying tissue
changes caused by inammation, demyelination, infection, and ischemia.
3
Another advanced imaging technique, which has been extensively adopted in brain cancer patients, is Positron
Emission Tomography (PET), a molecular imaging technique relying on the detection of emitted photons from radio-
tracers to provide dynamic functional molecular imaging. PET allows the assessment of biological processes, such as
glucose consumption and amino acid uptake non-invasively and quantitatively. Still, it is not suitable for revealing
structural aberrations in the white and gray matters. In addition, it has a low spatial resolution, cannot be used to detect
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Accepted: 29 April 2022
Published: 29 July 2022

rapid changes in brain activation, and has high costs due to its complex equipment.
4,5
Among the main advantages, PET
emerges for the possibility to co-register medical images with other imaging modalities.
The integration of these two techniques for the development of simultaneous multimodal imaging has become
particularly relevant in the oncology eld, where several diagnostic biomarkers can be combined to assess tumor
microenvironment.
6–10
Moreover, in recent years, an increase in the utilization of hybrid PET/MRI scanners has been
registered, allowing comparative metabolic and anatomical imaging at high resolution.
2,5,11
Indeed, PET/MRI is a tool
that combines simultaneously the high resolution provided by MRI for anatomical details and the high functional
sensitivity of PET. These coupled features appear to be signicantly advantageous over independent PET and MRI
examinations in better understanding tumor characteristics that could be useful for surgery and radiation therapy.
7,8,11–13
Studies show that PET/MRI and PET/CT perform equally well in oncology or that PET/MRI has minor to moderate
advantages over PET/CT.
14
In addition, compared to PET/CT, hybrid PET/MRI systems present higher costs for purchase,
installation, and maintenance and usually require longer scanning time.
14
However, besides the main advantages of the PET/
MRI lying in the decreased radiation dose and improved motion,
15
in the application to the brain pathologies, it has been
proved that PET/MRI offers an increased contrast of soft-tissue compared to PET/CT allowing to distinguish between grey
matter, white matter and cerebral spinal uid, providing a better anatomic contrast and boundaries denition.
6
Moreover,
through the use of specic sequences, complementary biological information such as cell density and apoptosis (diffusion-
weighted (DW) MRI) or angiogenesis (perfusion-weighted (PW) MRI) can be obtained.
3,6,7,10,13
In addition, the abnormal
uptake of a paramagnetic contrast agent (CA) can highlight possible pathological blood-brain-barrier (BBB) dysfunctions.
6,7
Instead, PET offers high sensitivity and specicity thanks to the possibility of using a wide range of tracers. According to the
tumor properties to analyse, a proper radiopharmaceutical should be used. [
18
F]uorodeoxyglucose ([
18
F]FDG) is the most
commonly used PET tracer due to the higher glucose metabolism that tumor cells exhibit compared to the surrounding
healthy tissues.
6,8,10
[
18
F]FDG crosses the BBB, being trapped in cancer cells after phosphorylation.
16
Indeed, in the early
1970s, researchers proved the ability of beta-emitting 14Cdeoxyglucose (DG) to cross the BBB.
17
Similarly to glucose, the
[
18
F]FDG is transported into cells via glucose transporters, and it is phosphorylated by the hexokinase system, but it cannot
be metabolized and, therefore, it persists in the tissue for an extended period of time as a polar metabolite.
18,19
This behavior
allows both mapping of regional function in the brain and visualizing tumor on FDG-PET scans. However, healthy brain
tissues have a high metabolism, leading to low tumor-brain contrast.
6
Despite the [
18
F]FDG is widely used in clinical
practice, it has a relatively low specicity and shows high background uptake by the normal brain. These limitations have
driven the development of amino acid PET tracers.
6,8,13
In fact, the unregulated protein synthesis in malignant tumors,
a symptom of an increased cell proliferation activity, can be highlighted by the elevated uptake of these amino acid
tracers.
6,8,10
Typical examples are O-(2-[
18
F]uoroethyl)-L-tyrosine ([
18
F]FET), 3,4-dihydroxy-6-[
18
F]-uoro
-L-phenylalanine ([
18
F]FDOPA), 3’-deoxy-3’-[
18
F]uorothymidine ([
18
F]FLT), and [
11
C]methionine ([
11
C]MET).
3,6,8,13,20
In particular, the [
18
F]FET is emerging as an optimal radiotracer to differentiate between low- and high-grade tumors with
high sensitivity (94%) and specicity (100%).
3,6,8,10,21,22
PET/MRI is becoming a well-established technique for brain tumor imaging thanks to the above-mentioned advantages.
Consequently, the choice of suitable PET tracers is essential for the specic clinical purpose. Simultaneously, MRI, both with
and without CAs, allows the investigation of the tumor also from a morphological perspective.
In the present work, we aim to provide a systematic review of the growing use of PET/MRI in the brain oncology
area, focusing the attention on the trend of PET tracers and MRI CAs, which are usually employed to perform hybrid
PET/MRI studies of brain tumors.
Materials and Methods
Eligibility Criteria
The literature review presented in this study was carried out in compliance with the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) 2015 guidelines. Only studies illustrating, at the same time, all the
following aspects were included in this review:
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●use of a hybrid PET/MRI diagnostic system;
●description of the PET/MRI protocol;
●focus on oncology applications;
●focus on brain oncology and related topics (eg studies on brain metastases generated by other types of tumors, or
phantom studies of brain tumors).
These inclusion criteria were used as the basis for the literature screening. Then, further renements to the search strategy
and specic exclusion criteria were applied, as detailed in the study selection paragraph.
Information Sources and Search Strategy
The following three electronic databases were used for an extensive literature search: PubMed, Scopus, and Web of
Science. All the mentioned databases were explored by using the following search strategy:
Title and Abstract containing the following keywords: (“pet-mr” OR “pet mr” OR “pet/mr” OR “pet-mri” OR “pet
mri” OR “pet/mri”) AND “brain” AND (“tumor” OR “tumors” OR “cancer” OR “cancers” OR “oncology”).
In addition, duplicate publications were removed, the search was limited to article-type publications only (reviews,
conference proceedings, book chapters and other types of publication were excluded), language was restricted to English
publications only.
Moreover, the search was dened in a specic time-frame: from 01 January 2012 to 31 January 2021. This is due to
the fact that the use of hybrid PET/MRI scanners has recently increased in the clinical Nuclear Medicine eld, with the
rst commercially available whole-body PET/MRI systems introduced and certied for routine clinical use in
January 2011, four years after the development of the prototype designed for brain imaging in 2007.
23,24
Even though
studies based on sequential PET and MRI acquisitions have been widely performed in the past, we aimed to investigate
only the most recent works focused on synchronous PET/MRI acquisitions, and therefore we decided to start the search
just one year after the establishment of hybrid PET/MRI scanners in the clinical practice. No further studies have been
collected from other external sources.
Study Selection
The study selection process was carried out in accordance with the PRISMA ow diagram. After the screening of the
databases, the duplicate publications removal, the selection of year, language, and publication type as described in the previous
paragraph, the full text of the selected articles were examined in order to check their eligibility according to the criteria
previously dened. In this phase, the full-text assessment was determined by the distinction between those articles using
a hybrid PET/MRI system and those acquiring sequential PET and MRI images for post-processing. The latter were then
excluded.
In addition, the full-text examination allowed us to discard further duplicates, non-English papers, conference
proceedings, and review articles that were not identied in the previous phases of the search.
Finally, a more in-depth reading of the full-texts enabled the exclusion of those studies not focused on brain oncology
and related topics (eg studies on brain metastases generated by other types of tumors, or phantom studies of brain
tumors), without providing accurate descriptions of the PET/MRI protocols, and with nal aims being out of the scope of
this systematic review.
Data Collection
Based on a customized Microsoft Excel form, data were collected linking to each paper the following information:
Name of the First Author, the Title of the Article, Year of Publication, Digital Object Identier (DOI) and Abstract. The
total number of papers, found at the end of the ltering phase, was equally divided between review authors. Possible
doubts about their categorization were discussed until a consensus was reached. Studies (such as conference papers,
reviews) were wrongly categorized by the electronic database as “articles” and so identied and excluded.
Successively, a second screening was carried out on the full-text articles to collect further information about the
study phase, tracers administered to perform PET/MRI and the oncological pathology of patients involved in the study.
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In particular, exploring the full-text articles allowed us to understand if PET/MRI brain images were acquired
simultaneously or not to discard cases where the inclusion criteria were not respected (for example, fusion images
after the acquisition with a single modality). No contact with the authors of the records for complementary information
was necessary.
Data Clustering
The data were initially divided into subgroups according to the study and validation phases: clinical, preclinical, and
phantom. However, a few were counted twice due to the presence in the same research of data belonging to two of the
previous subcategories. In addition, a further criterion was used to cluster studies depending on PET and MRI tracers.
Firstly, a division was created based on the use or not of the MRI CA. Despite the introduction of the PET/MRI hybrid
technology for more than 10 years, a double injection is performed using an agent for each diagnostic technique. In
particular, while the use of a tracer is essential for PET analysis, this is not true for MRI functioning since this latter
diagnostic technique is usually used as an anatomical reference to support PET modality. Among MRI CAs, gadolinium-
based ones are widely used in clinical practice covering almost the totality of the studies. Successively, both PET tracers
and MRI CAs were split into different categories. In the case of PET tracers, a distinction was made based on the nuclide
(mainly uorine-18, carbon-11 and gallium-68) and their labeling, while for MRI, more specically for gadolinium-based
CAs, the chelating agent was the clustering criterion.
Risk of Bias
Data derived from the studies were standardized using an Excel form agreed by reviewers after the exploration of full-
text articles in order to reduce possible biases. Moreover, a specic comments area for each article was created to allow
reviewers to report and discuss any doubts about the collocation in a specic category or possible exclusions. In addition,
a standardization was performed to group together the same agents differently named across studies (chemical name,
trade name or other synonyms).
Results Synthesis and Analysis
As previously described, two macro-categories were created based or not on the use of the MRI CA. In the presence of
the MRI CA, an additional group called “not specied” was created after widely noticing that in many studies the MRI
CA was not mentioned in the clinical protocol. The analysis of the collected data was carried out to bring out possible
variations or trends in the use of PET tracers, in combination or not with specic MRI CAs, also highlighting different
time intervals. The analysis was graphically represented, using OriginPro v2017 software, through histograms that
optimally show the distribution of numerical data. Moreover, these latter were often organized in panels with the aim to
help readers make comparisons between several data.
Results
Literature Search
The number of records found through the computer-based search is reported in Table 1.
A total number of 534 records were found from PubMed, Scopus, and Web of Science databases. The effective
number of records after duplicates removal was 257.
A computer-aided screening of the remaining records was carried out in three main steps, as briey reported in the
methodological section and outlined in Figure 1: (i) screening by year; (ii) screening by language; (iii) screening by
publication type.
After the automated screening, 129 full-text publications were examined by the reviewers to check the eligibility.
Among these publications, 75 articles were removed due to the following reasons:
●46 papers did not use a hybrid PET/MRI system;
●17 papers did not sufciently specify or describe the adopted PET/MRI protocol;
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●5 papers were out of the scope of this systematic review (no focus on brain oncology and related topics, eg studies
on brain metastases generated by other type of tumors, or phantom studies of brain tumors);
●5 papers were conference proceedings (not identied in the previous computer-aided screening);
●1 paper was a duplicate (not identied in the previous computer-aided screening);
●1 paper was written in non-English language (not identied in the previous computer-aided screening).
At the end of the selection process, the remaining 54 articles were included in both the qualitative and quantitative
syntheses.
The included articles present both clinical and preclinical studies as well as works on phantoms, as detailed in the
following Tables 2–4, respectively, which show the results of the literature search in alphabetical order (by the last name
of the rst author) with details on the year of the study, PET tracers, and MRI CAs used in the presented PET/MRI
protocol, as well as the focus of the study.
The overall distribution of the studies, divided into clinical, preclinical, and phantom, is shown in Figure 2 (additional
graphs regarding the types of study included and their geographical distribution are reported in the Supplementary
Materials, Figures S1–S3).
While Figure 2A shows the overall distribution of the selected studies, Figure 2B presents the same studies grouped
into three-time intervals (2012–2014, 2015–2017, 2018–2021) to reveal the increasing trend in the number of brain
oncology PET/MRI studies within the rst years from the introduction of the hybrid PET/MRI system (2012–2014) up to
the most recent works on this topic.
Table 1 Database Distribution of Found Records
Number of Records per Database Number of Total Records
PubMed Scopus Web of Science (with Duplicates) (without Duplicates)
158 213 163 534 257
Figure 1 Article selection process through the PRISMA ow diagram.
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Table 2 Clinical Studies Included in the Database
First Author Year PET Tracer MRI Contrast Agent Cases Discussed in the
Study
Akgun et al
25
2020 [
68
Ga]Ga-PSMA - Glial brain tumors
Anazodo et al
26
2015 [
18
F]FDG - Whole-brain imaging
Bashir et al
27
2020 [
18
F]FLT - Meningioma
Behr et al
28
2018 [
68
Ga]Ga-Citrate Gd-based contrast agent Glioma
Celebi et al
29
2020 [
18
F]FDG Gd-based contrast agent Brain lesion detection
Chen et al
30
2017 [
18
F]FDG - Glioblastoma
De Luca et al
31
2020 [
11
C]MET Gd-based contrast agent Brain tumors
Deuschl et al
32
2016 [
11
C]MET Gd-DOTA (Dotarem) Brain tumor
Deuschl et al
33
2018 [
11
C]MET Gd-DOTA (Dotarem) Glioma
Deuschl et al
34
2017 [
18
F]FDG Gd-DOTA (Dotarem) Brain metastases
Filss et al
35
2014 [
18
F]FET Gd-DOTA (Dotarem) Glioma
Franceschi et al
36
2018 [
18
F]FDG - Brain investigation
Gauvain et al
37
2018 [
18
F]FDOPA - Pediatric brain tumor
Gerstner et al
38
2020 [
11
C]TMZ Gd-DTPA (Magnevist) Glioblastoma
Haubold et al
39
2020 [
18
F]FET Gd-DOTA (Dotarem) Glioma
Ho et al
40
2019 [
18
F]FDG MRI paramagnetic contrast
agent
Brain metastases
Ishii et al
41
2015 [
18
F]FDG - Brain metastatic lesions
Izquierdo-Garcia
et al
42
2014 [
18
F]FDG
[
18
F]FET
- Glioblastoma
Jena et al
43
2014 [
18
F]FDG - Brain lesion detection
Karlberg et al
44
2017 [
18
F]uciclovine - Glioma
Kikuchi et al
45
2020 [
18
F]FDG - Brain tumors
Ladefoged et al
46
2017 [
18
F]FET - Glioma
Intracerebral metastasis
Ladefoged et al
47
2019 [
18
F]FET - Brain tumor
Lee et al
48
2016 [
18
F]FDG Gd-DOTA (Dotarem) Brain metastases
Marner et al
49
2019 [
18
F]FET - Brain tumor
Mehranian et al
50
2017 [
18
F]orbetaben
[
18
F]FDG
- Image reconstruction
Melsaether et al
51
2016 [
18
F]FDG Gd-DTPA (Magnevist) Brain metastasis
Muehe et al
52
2020 [
18
F]FDG Ferumoxytol (Feraheme) Tracer uptake in brain
regions
Ponisio et al
53
2020 [
18
F]FDOPA Gd-BOPTA (MultiHance) Glioma
(Continued)
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PET/MRI Studies with and without MRI Contrast Agents
The selected articles have been divided making a distinction between PET/MRI studies where the only PET tracer is
included in the protocol from those where an MRI CA is additionally used (Figure 3).
Table 2 (Continued).
First Author Year PET Tracer MRI Contrast Agent Cases Discussed in the
Study
Preuss et al
54
2014 [
11
C]MET - Pediatric brain tumor
Pyatigorskaya
et al
55
2020 [
18
F]FDG MRI contrast agent (not
specied)
Glioma
Rausch et al
12
2017 [
18
F]FDG
[
18
F]FET
[
68
Ga]Ga-DOTA-NOC
- Brain tumor
Rausch et al
56
2019 [
18
F]FET - Glioma
Roytman et al
57
2020 [
68
Ga]Ga-DOTA-TATE - Meningioma
Ruhlmann et al
58
2016 [
18
F]FDG Gd-BT-DO3A (Gadovist) Tracer uptake in the brain
Sacconi et al
59
2016 [
18
F]FET Gd-BT-DO3A (Gadovist) Brain tumors
Schwenzer et al
60
2012 [
18
F]FDG
[
11
C]MET
[
68
Ga]Ga-DOTA-TOC
- Glioma
Head and upper neck
tumors
Shankar et al
61
2020 [
18
F]FCho
[
18
F]FDOPA
- Glioma
Intracranial germ cell
tumors
Primitive neuroectodermal
tumors
Slipsager et al
62
2019 [
18
F]FET Gd-BT-DO3A (Gadovist) Healthy patients
Sogani et al
63
2017 [
18
F]FET - Glioma
Song et al
64
2020 [
18
F]FET Gd-based contrast agent Glioma
Song et al
65
2020 [
18
F]FET Gd-DTPA (Magnevist) Glioma
Starzer et al
66
2021 [
68
Ga]Ga-Pentixafor Gd-based contrast agent Central nervous system
lymphoma
Stegger et al
67
2012 [
11
C]MET
[
68
Ga]Ga-DOTA-TOC
- Intracranial tumors
Theruvath et al
68
2017 [
18
F]FDG - Tissue injuries of the brain
Verger et al
69
2017 [
18
F]FET Gd-DOTA (Dotarem) Glioma
Yan et al
70
2013 [
18
F]FDG - Cervical cancer
Young et al
71
2020 [
18
F]F-PARPi Gd-BT-DO3A (Gadovist) Brain cancer
Brain lesion
Zhang et al
72
2019 [
68
Ga]Ga-NOTA-Aca-
BBN(7–14)
- Glioma
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Taking into account the overall distribution of articles without any distinction between clinical, preclinical and
phantom studies, there seems to be a slight tendency to use the only PET tracers (see Figure 3A). However, looking in
detail at the three time intervals (Figure 3B), an increasing trend in the use of both agents to support the clinical analysis
Table 4 Phantom Studies Included in the Database
First Author Year PET Tracer MRI Contrast Agent Cases Discussed in the
Study
Bland et al
75
2019 [
18
F]FDG - Brain image reconstruction
Harries et al
76
2020 [
18
F]FDG - Simulation
Ko et al
73
2016 [
64
Cu]Cu-NOTA-IO-MAN
[
18
F]FDG
[
11
C]MET
[
64
Cu]Cu-NOTA-IO-MAN Brain metabolic function
Mehranian et al
50
2017 [
18
F]orbetaben
[
18
F]FDG
- Image reconstruction
Wampl et al
77
2017 [
18
F]FDG
[
18
F]FET
- Simulation
Table 3 Preclinical Studies Included in the Database
First Author Year PET Tracer MRI Contrast Agent Cases Discussed in
the Study
Behr et al
28
2018 [
68
Ga]Ga-Citrate Gd-based contrast agent Glioma
Ko et al
73
2016 [
64
Cu]Cu-NOTA-IO-MAN
[
18
F]FDG
[
11
C]MET
[
64
Cu]Cu-NOTA-IO-MAN Brain metabolic function
Schröder et al
74
2015 [
18
F]F-TA3
[
18
F]F-TA4
- Molecular imaging
Young et al
71
2020 [
18
F]F-PARPi Gd-BT-DO3A
(Gadovist)
Animal glioma model
Figure 2 Articles distribution based on the type of study in the whole (A) and in three specic time frames (B) (2012–2014, 2015–2017, 2018–2021).
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comes out. In fact, the ratio has grown from 6 to 0.86 in the last years in favor of “PET and MRI tracers” category,
demonstrating the importance for clinicians to enhance image contrast for both modalities to better visualize possible
functional and anatomical alterations.
PET Tracers Used in PET/MRI with and without MRI Contrast Agents
A more focused analysis of the PET tracers has been successively carried out to highlight possible trends in the use of
specic tracers in the presence or not of an MRI CA (Figure 4).
Firstly, a distinction has been made according to the PET molecule’s radioisotope. Indeed, as shown in Figure 4A and C,
it is evident that, in both gures, uorine-18 is the most widely used (around 77% in Figure 4A and around 69% in
Figure 4C). The remaining percentage is shared between gallium-68 and carbon-11 radioisotopes, the former being more
used in the absence of MRI CAs (Figure 4A) while the latter in the presence of MRI CAs (Figure 4C). In fact, the gallium-
68 radioisotope is more present in studies based only on PET tracers to the detriment of the carbon-11 radioisotope
(Figure 4C). The introduction of an MRI CA (Figure 4A) produces percentage changes from 7.5% to 19.23% and from
15% to 7.69% for carbon-11 and gallium-68, respectively. A special mention is made for the [
64
Cu]Cu-NOTA-IO-MAN
tracer that represents the only multimodal one, among all the selected studies, able to provide contrast for both PET and
MRI modalities at the same time.
73
It represents an example of the growing research trend moving towards the design of
multimodal imaging probes.
An insight into each radioisotope category has been performed in order to understand the ligands mostly employed in
protocols (see Figure 4B and D). Regarding the uorine-18 radioisotope, [
18
F]FDG is the most widely used ligand,
followed by [
18
F]FET. However, a growing use of the latter over time can be observed in Figure 5.
In particular, in the “PET tracers without MRI CA” category, the [
18
F]FDG remains the most used tracer in the
examined studies over time. On the other side, in the presence of MRI CAs, the temporal trend shows how [
18
F]FET is
increasingly used, in step with [
18
F]FDG within the most recent time window (2018–2021). In the case of carbon-11, the
MET ligand covers almost all the studies (only one protocol with [
11
C]temozolomide, [
11
C]TMZ, has been found). For
the gallium-68, a uniform distribution of different ligands can be observed over time.
MRI Contrast Agents Used in PET/MRI
Gadolinium-based CAs are the most widely used MRI contrast enhancers even in hybrid PET/MRI protocols, as
displayed in Figure 6.
Figure 3 Numerical comparison between studies performing PET/MRI acquisitions after the administration of the PET tracer with or without the MRI CA, in the whole (A)
and in three specic time frames (B) (2012–2014, 2015–2017, 2018–2021).
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As from Figure 6A, 62.5% of the overall MRI CAs used in PET/MRI studies include gadolinium-based CAs. In
particular, Dotarem is present in selected studies in a percentage equal to 29.1%, followed by Gadovist at 16.7%, and
then Magnevist at 12.5%. In addition to the [
64
Cu]Cu-NOTA-IO-MAN, previously mentioned, only one protocol with an
iron-based MRI CA (Feraheme) has been found.
52
Moreover, when looking at Figure 6A, a slice of around 29% is
labeled as “Not specied” since it refers to those studies where the MRI CA was not explicitly dened in the protocol.
From an insight into the temporal trend, again divided into three-time windows (Figure 6B), it does not emerge
a preference for the use of MRI CAs in PET/MRI protocols over the years.
Finally, in Figure 7, the three leading MRI CAs (Dotarem, Magnevist and Gadovist) are related to the corresponding
PET tracer used in the same study protocol. When looking at column colors, the radioisotope uorine-18 is largely
employed, with a slightly higher preference for [
18
F]FET rather than for the [
18
F]FDG, widely used in studies without
MRI CAs. In addition, carbon-11 is used in three studies, while nowhere else the radioisotope gallium-68 is used in
combination with one of these three MRI CAs.
Discussion and Conclusions
We have systematically reviewed the use of the PET tracers and MRI CAs as employed in hybrid PET/MRI imaging
studies of the brain, with a specic focus on the oncology eld. The most widely used PET imaging approaches target the
Figure 4 PET tracers numerical distribution based on the radioisotope with (A and B) or without (C and D) a MRI CA (green, blue, orange and yellow colors are attributed
to uorine-18, carbon-11, gallium-68 and copper-64 radioisotopes, respectively.
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glycolytic ux using [
18
F]FDG, highly used for neurological applications. However, the increasing understanding of
tumorigenesis has fostered the development of several imaging strategies intended to visualize tumor burden more
specically. Many radiotracers better delineate malignant cells than [
18
F]FDG, which does not detect malignant tissue
with a high degree of sensitivity or specicity and has high background brain uptake. Nevertheless, those radiotracers
that have been evaluated after chemoradiation also have shown uptake in nonmalignant processes, and their specicity
for cancer is currently estimated to be between 60% and 90%.
In recent years, interest has increased towards the use of amino acid tracers, such as [
18
F]FET, for tumor grading,
treatment planning, biopsy guidance, and glioma imaging for prognosis and treatment response assessment.
12
The
amino acid tracer FET was used in 27.8% of the total reviewed works. It may play a more critical role than FDG in
imaging gliomas and meningioma because it can identify tumor borders with superior tumor-to-background contrast
providing clearer borders of lesions.
12,65
A major advantage of these tracers is their ability to cross the intact BBB
through amino acid transport, as conrmed by several recent studies, revealing that areas with increased FET uptake
Figure 5 Categorization of PET tracers used in three specic time frames both in presence and not of the MRI CA.
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correspond to the tumor cell distribution.
64
Another amino acid tracer is the [
18
F]FDOPA, which has a 5.55% response
in the articles viewed. The uptake of [
18
F]FDOPA in the normal brain is relatively low, improving visualization of low-
grade tumors, delineating the extent of the tumor, differentiating neoplastic from non-neoplastic tissue and predicting
response to therapy. Tumor cell uptake of [
18
F]FDOPA utilizes a transporter upregulated in brain tumors.
37
Among the
Figure 6 Type of MRI CA administered together with a PET tracer in the whole (A) and in three specic time frames (B) (the “Not specied” category is referred to
articles where the MRI CA is not well dened although it is used in the study).
Figure 7 PET tracers used in protocols where one of the three most used MRI CAs is present.
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different amino acid tracers [
11
C]MET PET is well characterized for the evaluation of glioma, especially for hypo- or
isometabolic lesions, and has been available for the last decades in clinical routine (found in 12.96% of papers) as it is
convenient and efcient in its radiochemical production. The uptake of [
11
C]MET is mediated by the neutral L-amino
acid transporter that serves the increased demand for amino acids in tumor cells. The distribution of [
11
C]MET has
potential to characterise primary brain tumor/metastases, assess the efcacy of oncological treatment and differentiate
radionecrosis from tumor recurrence. [
11
C]MET PET has been shown in previous studies to identify suspected/
recurrent glioma with high sensitivity (range 96–100%), specicity (range 60–88%) and diagnostic accuracy (range
82–94%).
33
Compared with [
18
F]FDG, amino acid PET tracers, such as [
11
C]MET, [
18
F]FET and [
18
F]FDOPA, exhibit lower
uptake in a healthy brain, do not depend on the compromise of the BBB and present clearer tumor borders with higher
tumor-to-background contrast. In particular, the half-life of uorine-18 (110 min) is longer than that of carbon-11 (20
min), making [
18
F]FET more suitable for routine clinical applications in neuro-oncology. Furthermore, FET has high
in vivo stability and is efciently synthesized by nucleophilic reactions. In addition, unlike contrast-enhanced MRI,
radiolabeled amino acid tracers can visualize both contrast-enhancing and non-enhancing brain tumors. These biological
properties, improving estimation and delineation of tumor margins, have important implications for resection, biopsy, and
radiation treatment.
Since 2018, new emerging tracers have been added to those most commonly used. With about 18% use of tracers,
[
68
Ga]Ga-Citrate, a Fe
3+
biomimetic that binds to apo-transferrin in the blood, can detect high-grade glioma in adults and
children.
72
Moreover, this latter can also be used to develop targeted internal radiation therapies.
25
Cancer cells generally
have an elevated demand for Fe
3+
, an essential nutrient required for various biochemical processes associated with cell
growth and proliferation.
28
Among the most recently used PET tracers, [
68
Ga]Ga-Pentixafor targets specically the
CXCR4 receptor and has been applied to lymphoma, leukemia, and myeloma. Although [
68
Ga]Ga-Pentixafor cannot
penetrate the intact BBB, the latter is impaired in patients with brain tumors.
66
In light of what has been outlined above, despite the availability of different PET tracers, both in combination with
MRI CAs or alone, it emerges that [
18
F]FDG remains the most important tracer for PET/MRI, as also conrmed in
previous investigations rating it among the top 3 tracers used in clinical practice and especially in cancer imaging, despite
some limitations for specic cancer types.
9,23,78
Moreover, an additional point emerges from the analysis of the selected
studies: the lack of multimodal contrast media. In fact, to the best of our knowledge, the use of the PET/MRI system is
rarely associated with a hybrid compound able to provide image contrast for both PET and MRI at the same time. Despite
the development of multimodal contrast media as one of the main research topics in the biomedical area, it appears that
multimodal probes for hybrid PET/MRI in the brain are not mature enough. In this regard, the literature on the design of
multimodal imaging agents goes in two main directions: the rst one consists of the elaboration of new chemical
formulations; the second one aims to synthesize nanovectors able to simultaneously encapsulate and carry two or more
CAs or tracers that are used in the clinical practice. Examples of such nanosystems for the encapsulation of a specic
contrast medium are widely available in the literature, with particular regard to MRI CAs, and showed to bring additional
advantages like the improvement of the contrast-enhancing properties and the targeting capability obtained by means of
surface decoration and functionalization.
79–89
More efforts are now devoted to developing nanocarriers for multimodal
imaging purposes, especially for MRI/optical imaging, MRI/CT, and PET/MRI applications.
84,90–97
However, in the case
of PET/MRI, the development of these hybrid contrast media is particularly limited by the short half-life of PET tracers.
In fact, the need for a cyclotron or a linear accelerator is already a problem in a single PET modality. Consequently, the
development of more complex nanosystems exacerbates these difculties. This consideration could lead to the choice of
radionuclides with a longer half-life, such as copper-64, without forgetting that a prolonged circulation time in the human
body could be harmful as well.
In conclusion, taking into account the technical advancements in hybrid PET-MRI and its growing clinical value in
the neuro-oncology area, it can be observed that there is still variability in the use of PET tracers and MRI CAs, alone or
in combination, during PET/MRI protocols for brain tumor investigation, despite standardized protocols can be identied
for specic diseases and diagnostic questions. Furthermore, while most widely used PET tracers can be identied in the
two categories of [
18
F]FDG and [
18
F]FET, the temporal evolution of the acquisition techniques and the clinical and
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research advancements over the years have left space for different additional tracers. As far as the MRI CAs, while the
gadolinium-based ones, remain mainly used also in PET/MRI studies, there seems to be no preferred combination of PET
tracers in hybrid PET/MRI studies. Finally, the present study suggests that perspective research efforts could be devoted
to a better denition of the role of tracers and CAs in both clinical and preclinical hybrid PET/MRI applications, also
given the newly emerging imaging agents and the need for novel multimodal nanoprobes.
Disclosure
The authors report no conicts of interest in this work.
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