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E. Lopci, L. Mansi (eds.), Advanced Imaging and Therapy in Neuro-Oncology,

https://doi.org/10.1007/978-3-031-59341-3_3

Positron Emission Tomography

fromFDG toAmino Acid Tracers

ArnoldoPiccardo, ValentinaGaribotto,

AngeloCastello, FrancescoCicone,

FrancescoGiammarile, LuigiaFlorimonte,

RobertoC.DelgadoBolton, LuigiMansi,

andEgestaLopci

3.1 Imaging Brain Tumors

withPET

Brain tumors, i.e., tumors of the central nervous

system (CNS), include both primary lesions and

metastases to the CNS.

Primary CNS tumors are rare tumors, with an

approximate incidence of 12 per 100,000 persons

per year [1]. The most common malignant pri-

mary tumor is glioblastoma (15% of primary

CNS tumors), followed by primary CNS lympho-

mas, while the most common benign tumors are

meningiomas (38% of primary CNS tumors).

The latest World Health Organisation (WHO)

classication of primary brain tumors published

in 2021 classies gliomas on the basis of their

combined genetic and histological characteris-

tics, as rst introduced in the 2016 edition, and

distinguishes adult-type diffuse gliomas,

pediatric- type diffuse low-grade gliomas,

A. Piccardo

Department of Nuclear Medicine, Galliera Hospital,

Genoa, Italy

e-mail: arnoldo.piccardo@galliera.it

V. Garibotto

Division of Nuclear Medicine and Molecular Imaging,

Geneva University Hospitals, Geneva, Switzerland

NIMTLab, Geneva University, Geneva, Switzerland

e-mail: valentina.garibotto@hcuge.ch

A. Castello · L. Florimonte

Nuclear Medicine Unit, Fondazione IRCCS Ca’

Granda, Ospedale Maggiore Policlinico, Milan, Italy

e-mail: angelo.castello@policlinico.mi.it;

luigia.orimonte@policlinico.mi.it

F. Cicone

Department of Experimental and Clinical Medicine,

Neuroscience Research Centre, PET/RM Unit,

“Magna Graecia” University of Catanzaro,

Catanzaro, Italy

Nuclear Medicine Unit, University Hospital “Mater

Domini”, Catanzaro, Italy

e-mail: cicone@unicz.it

F. Giammarile

Nuclear Medicine and Diagnostic Imaging Section,

Division of Human Health, Department of Nuclear

Sciences and Applications, International Atomic

Energy Agency (IAEA), Vienna, Austria

e-mail: f.giammarile@iaea.org

R. C. DelgadoBolton

Department of Diagnostic Imaging (Radiology) and

Nuclear Medicine, University Hospital San Pedro,

Centre for Biomedical Research of La Rioja (CIBIR),

Logroño, Spain

Servicio Cántabro de Salud, Santander, Spain

e-mail: robertocarlos.delgado@scsalud.es

L. Mansi

Section Health and Development, Interuniversity

Research Center for Sustainable Development

(CIRPS), Napoli, Italy

e-mail: Luigi.MANSI@unicampania.it

E. Lopci (*)

Nuclear Medicine Unit, IRCCS-Humanitas Research

Hospital, Rozzano, Milano, Italy

e-mail: egesta.lopci@humanitas.it

https://t.me/med1917

pediatric- type diffuse high-grade gliomas, and

circumscribed astrocytic gliomas [2]. Emphasis

is added to the identication of mutations also

beyond isocitrate dehydrogenase 1 (IDH1) in dif-

fuse gliomas, especially in young patients below

55years of age.

Brain metastases are more than ten times more

frequent than primary CNS tumors and mainly

associated with lung cancer, breast cancer, and

melanoma [3].

The routine workup of brain lesions is based

on MRI, which is recommended to complement

the evaluation of lesions identied during a sys-

temic workup (with CT or PET/CT) for a primary

tumor or during the investigations related to the

presence of symptoms possibly related to intra-

cerebral masses. MRI shows an excellent tissue

contrast and identies lesion characteristics and

extension, including cellularity and tissue inl-

tration, as well as blood-brain barrier (BBB)

leakage evaluating contrast enhancement.

Advanced MR imaging includes diffusion tensor

imaging and spectroscopy, for example, allowing

a multiparametric tissue characterization [4].

There are however a number of specic indi-

cations in which molecular imaging might be of

help, namely differential diagnosis of benign

lesions and post-treatment changes from malig-

nant lesions, biopsy targeting and tumor grading,

and the denition of tumor extent in a pre- surgical

or pre-radiation therapy setting. One of the main

advantages of PET imaging is that the most fre-

quently used radiopharmaceutical inux is inde-

pendent of the BBB integrity [5].

Among PET radiopharmaceuticals, 2-deoxy- 2-

[

F]uoro--glucose (2-[

F]FDG) remains by far

the most largely used in oncology. The rational for

its use is based on the large energy requirement of

malignant cells, and brain metastases and high-

grade primary brain tumors are no exception. The

increased glycolytic metabolism of the cells

induces overexpression of GLUT-1 transporters

and hexokinase, which determines the increased

2-[

F]FDG uptake and intracellular trapping.

Silent brain lesions can be identied on the

brain acquisition during whole body 2-[

F]FDG

PET investigations, highlighting the importance

of including the whole brain in oncological FDG

acquisitions [6].

However, the brain tissue is physiologically

characterized by a high density of GLUT-3

transporters on neurons and glial cells, namely

astrocytes, determining the high tissue back-

ground that limits the applicability of 2-[

FDG PET imaging to detect and characterize

brain lesions. In addition, some inammatory

lesions in the brain might exhibit high 2-[

FDG uptake [7].

This represents an issue mainly for low-grade

lesions/tumors, in which FDG uptake is close to

or lower than the physiologic uptake by the

white matter [8, 9]. The ability of 2-[

F]FDG

PET to provide information associated with the

grade of brain lesions and an associated worse

prognosis and disease progression is thus well

established [8, 10, 11]. The association of 2-[

FDG uptake and tumor grade could also support

its use to select the site for biopsy targeting, as

tumor prognosis is obviously guided by its high-

est grade component. However, the denition of

specic thresholds to distinguish high and low-

grade gliomas is hindered by the fact that there is

a large overlap in 2-[

F]FDG uptake of these

two categories [12]. In addition, there are rele-

vant exceptions of low-grade tumors with high

2-[

F]FDG uptake, namely pilocyic astrocyto-

mas [13].

2-[

F]FDG PET is typically positive in

case of recurrence of a high-grade tumor (pri-

mary tumor or metastases) (Fig. 3.1) while

negative in case of post-radiation therapy

changes, with variable sensitivity and speci-

ficity values reported in the literature [14, 15].

The reference tissue to define positive or nega-

tive uptake is usually the normal brain tissue,

considering negative lesions with an uptake

inferior or equal to the white matter uptake

and positive lesions with an uptake higher than

the cortex. This clearly leaves a large undeter-

mined range for lesions with an uptake inter-

mediate between white and gray matter that

can ultimately be recurrent tumor, radiation

necrosis, or a combination of both [12]. Some

authors have suggested the use of dual-phase

acquisitions for this purpose, with variable

intervals between the two phases, ranging

from 2 h to more than 5h, and thus with lim-

ited applicability [16].

A. Piccardo et al.

https://t.me/med1917

Fig. 3.1 Patient with suspected glioblastoma (GBM) and

previous breast cancer investigated with 2-[

F]FDG PET

(a, d, fused PET/CT; b, e, axial PET) and Gd-enhanced

MRI (c, f). Note the very faint uptake in the right subcorti-

cal frontal region highlighted with the red circle (a, b, d,

e), corresponding to the circumscribed area of enhance-

ment on RMN (c, f)

The performance of 2-[

F]FDG PET for this

indication has overall been shown to be inferior

to other imaging methods, such as amino acid

PET and advanced MRI [17].

Finally, 2-[

F]FDG PET might be one of the

best molecular imaging modalities for the inves-

tigation of suspected primary brain lymphomas.

Brain lymphoma is characteristically strongly

FDG-avid, and this feature has the potential to

distinguish them not only from non-tumoral

lesions but also from high-grade gliomas and

brain metastases [18]. 2-[

F]FDG PET can also

distinguish lymphoma from opportunistic infec-

tions in immunocompromised patients, with a

better performance than SPECT or MR spec-

troscopy [19]. 2-[

F]FDG PET can also be of

help for the evaluation of the response in pri-

mary CNS lymphomas to chemotherapy, namely

because of the high negative predictive value of

interim 2-[

F]FDG PET, that could thus be of

added value in determining the duration for

induction therapy, namely in those patients not

achieving a complete response on MRI [5].

Importantly, current recommendations from the

International Primary CNS Lymphoma

Collaborative group recommend a whole-body

2-[

F]FDG PET examination in patients with

lymphomatous brain lesions, in order to identify

systemic lymphomas [20].

2-[

F]FDG PET imaging can be acquired in

static modality, with an acquisition starting 45min

after tracer administration following standard rec-

ommendations, or dynamically, with the acquisition

starting at injection and lasting 60min [12, 21].

A dynamic acquisition allows measuring addi-

tional parameters, namely the regional metabolic

3 Positron Emission Tomography fromFDG toAmino Acid Tracers

https://t.me/med1917

rate (MRglu), which is a more accurate estimate of

glucose consumption in the tissue than the standard-

ized uptake value (SUV), which can be assessed

with a static acquisition [12]. Discrepancies between

SUV and MRglu are mainly observed during and

after therapy, as treatments can change the relative

equilibrium of the radiopharmaceutical between the

circulating and tissular compartments. Thus a

dynamic investigation is recommended when test-

ing novel treatments, whose impact on tracer avail-

ability is unknown. There is currently no indication

in which dynamic scanning for 2-[

F]FDG PET

imaging for brain lesions has been proven to be

superior to static scanning.

Overall, although 2-[

F]FDG PET has estab-

lished diagnostic and prognostic abilities in brain

tumors with intense 2-[

F]FDG uptake and in the

context of tumor recurrence, in current guidelines

there is no specic indication in which 2-[

FDG PET is preferred over amino acid PET

imaging [12, 17, 21, 22].

3.2 The Role of[

C]MET

inPrimitive andSecondary

Brain Tumors

The use of radiolabelled amino acids has emerged

as an essential tool for detecting and characteriz-

ing brain tumors. Amino acid tracers are particu-

larly accurate for the distinction between tumor

recurrence and radiation necrosis, which repre-

sents the single most common indication in the

clinical management of brain tumor patients. In

particular, methyl-

C--methionine ([

C]MET)

is an example of radiopharmaceuticals utilized

for brain tumors imaging, since cancer cells pres-

ent an overexpressed amino acid transporter sys-

tems, resulting in altered tumor vasculature and

tumor cell proliferation [12]. This overexpression

allows for radiolabelled amino acids, including

[

C]MET, 2-[

F]uoroethyl)--tyrosine ([

FET), and 3,4-dihydroxy-6-[

F]uoro--

phenylalanine ([

F]DOPA), to achieve a superior

target- to-background ratio compared to 2-[

FDG in the diagnosis of brain tumors [12, 23,

24].

Methionine uptake primarily occurs through a

sodium-independent transporter that facilitates the

movement of the amino acid into cells [25]. This

transport process is driven by a concentration gradi-

ent and is inuenced by the amino acid’s metabo-

lism within cells, which is directly linked to cellular

proliferation. Studies have demonstrated that

tumors of various types avidly accumulate methio-

nine [26]. Subsequent to administration, methionine

uptake in the brain is generally low, varying depend-

ing on the anatomical region and age [27, 28]. This,

combined with high tumor uptake, highlights the

potential of methionine for imaging brain tumors,

offering the prospect of enhanced tumor detection

and lesion delineation [29]. The underlying contrast

between tumors and normal brain tissue on methio-

nine imaging appears to be attributed to an aug-

mented amino acid transport mechanism. Various

subtypes of amino acid transporter systems have

been identied, including LAT1, LAT2, and LAT3,

each mediating L-transport. Interestingly, one of

these subtypes (LAT2) is expressed specically in

tumor cells but not in inammatory cells [30].

Amino acid brain tumor imaging, comprising

[

C]MET, can be employed for various diagnos-

tic and therapeutic purposes [12]. In accordance

with the Joint EANM/EANO/RANO practice

guidelines/SNMMI procedure standards [12],

most common indications for PET imaging in

primary brain tumors can be summarized in

Table3.1.

Table 3.1 Principal indications of amino acid PET tracers for imaging primary brain tumors

Timing Indication

At primary diagnosis Differentiation of grade III and IV tumors from not neoplastic lesions or grade

I and II gliomas

Prognostication of gliomas

Denition of the optimal biopsy site (e.g., site of maximum tracer uptake)

Delineation of tumor extent for surgery and radiotherapy planning

Diagnosis of tumor recurrence Differentiation of glioma recurrence from treatment-induced changes, e.g.,

pseudoprogression and radionecrosis

Disease and therapy monitoring Assessment of response after local or systemic treatment

A. Piccardo et al.

https://t.me/med1917

3.2.1 [

C]MET PET inPrimary

Gliomas Diagnosis

Numerous studies have assessed the diagnostic

accuracy of [

C]MET PET in differentiating

presumed gliomas (Fig.3.2). Overall, sensitivi-

ties ranging from 76% to 100% were observed,

encompassing both low-grade and high-grade

gliomas [31–41]. Notably, sensitivity tended to

be lower in studies with a higher proportion of

low-grade gliomas. For instance, the study by

Herholz et al. exhibiting the lowest sensitivity

involved a majority of patients suspected of har-

boring low-grade gliomas [36]. Alongside the

generally satisfactory sensitivities reported,

[

C]MET PET has demonstrated remarkable

specicity in distinguishing non-tumoral brain

lesions from gliomas, ranging from 75% to

100% [32–34, 36, 38, 39, 42, 43]. Nevertheless,

false- positive ndings have been encountered in

certain studies, including necrosis, leucoen-

cephalitis, brain abscesses, hematoma, isch-

emia, and demyelination.

Of paramount importance to clinicians is the

overall diagnostic accuracy, which has only been

reported in studies by Herholz etal. [36] (79%),

Yamane et al. [43] (81%), and Li et al. [39]

(86%). Braun etal. [32] obtained a high positive

predictive value of 96% but a low negative pre-

dictive value of 43%. Yamane et al. made an

important observation by examining the planned

therapy prior to the scan and the nal treatment

following the scan results. In 20 patients with

suspected gliomas, the scan outcomes altered the

initial management strategy in 63% [43].

Generally, [

C]MET uptake is lower in low-

grade gliomas compared to high-grade gliomas,

although signicant overlap exists between the

two groups. Most studies employed a T/N ratio to

determine sensitivity and specicity. However,

the cut-off ratios employed varied from 1.3 to

2.05 [25, 31, 34, 38, 39] (Table3.2).

The prevailing opinion among experts is that

[

C]MET PET is superior to 2-[

F]FDG PET for

imaging brain tumors and metastases. [

C]MET

PET offers greater sensitivity compared to 2-[

FDG PET, particularly in low-grade gliomas

[44]. Observed sensitivity of 100% was reported

for [

C]MET PET compared to 40% for 2-[

FDG [45].

[

C]MET PET consistently demonstrates

superior diagnostic accuracy compared to [

FET PET in gliomas, particularly for low-grade

gliomas. Studies have reported sensitivities for

[

C]MET PET ranging from 76% to 100% in

low-grade gliomas, while [

F]FET PET

sensitivities typically range from 60% to 80%

[31–41]. Additionally, [

C]MET PET is superior

to [

F]DOPA PET whose sensitivities range

from 70% to 80% [36, 38, 41]. This enhanced

Fig. 3.2 Patient with focal cortical dysplasia on the

left temporal lobe, highlighted with the red circle on

[

C]MET PET/CT (SUVmax 1.5; SUVratio 1.15): (a)

axial low-dose CT, (b) axial [

C]MET PET, and (c)

fused PET/CT axial image of the lesion

3 Positron Emission Tomography fromFDG toAmino Acid Tracers

https://t.me/med1917

Table 3.2 Commonly used thresholds for amino acid PET, validated histologically or clinically, according to the clini-

cal question

Clinical indications Tracers Variables Thresholds

Differentiation between neoplastic and

non-neoplastic tissue

[

F]FET TBRmax 2.5

TBRmean 1.9

[

C]MET TBRmax 1.3–1.5

[

F]DOPA – n.a.

Tumor grading (grade I/II versus III/IV

glioma)

[

F]FET TBRmean 1.9–2.0

TBRmax 2.5–2.7

TTP <35min

TAC pattern (I, II, III) Pattern II, III

Tumor extent [

F]FET TBR 1.6

[

C]MET TBR 1.3

[

F]DOPA TBR 2.0

Tumor recurrence [

F]FET TBRmean (circular ROI diameter 1.6cm) 2.0

TTP <45min

[

C]MET TBRmax 1.6

[

F]DOPA TSRmax 2.1

TSRmean 1.8

Malignant transformation of grade I/II

glioma

[

F]FET TBRmax >33%

increase

TBRmean >13%

increase

TTP change in ROI >1.6 brain 6min

decrease

Differentiation between early

pseudoprogression and true progression

[

F]FET TBRmax 2.3

Differentiation between late

pseudoprogression and true progression

[

F]FET TBRmax 1.9

TBRmean 1.9

Identication of responders in

treatment response evaluation

[

F]FET Radiochemotherapy

(7–10days)

TBRmax >20%

decrease

TBRmean >5% decrease

Bevacizumab/irinotecan

(4–12weeks)

BTV >45%

decrease

[

C]MET Temozolomide TBRmax Stable or

decreasing

[

F]DOPA Bevacizumab (2weeks) BTV >35%

decrease

<18mL

TBR tumor to background ratio, TTP time to peak, TAC time-activity curve, TSR tumor to striatum ratio, ROI region of

interest

Modied from Law I etal. [12] under the terms of the Creative Commons Attribution 4.0 International License (http://

creativecommons.org/licenses/by/4.0/)

A. Piccardo et al.

https://t.me/med1917

sensitivity of [

C]MET PET stems from its avid

uptake by proliferating cells, which are more

prevalent in low-grade gliomas.

3.2.2 Prognosis ofPatients

withPrimary Gliomas

Conventionally accepted prognostic factors for

glioma patients include tumor grade, age, perfor-

mance status, proliferation indices, like Ki-67,

and molecular status. In this context, [

C]MET

PET has been shown to be an independent prog-

nostic factor in gliomas, while the prognostic

value of [

F]FET PET and [

F]DOPA PET is

less well-established. Smits et al. observed that

patients with high-risk low-grade glioma and

high [

C]MET uptake exhibited a poorer prog-

nosis compared to those with high-risk glioma

and low [

C]MET uptake, implying the potential

of [

C]MET PET for prognostication [25, 46].

Nariai etal. established a signicant correlation

between survival and pretreatment tumor-to-

normal (T/N) ratio [47]. Kim etal. corroborated

these ndings, concluding that [

C]MET PET

acts as an independent prognostic factor and may

be employed as a biological prognostic marker

[48]. Ribom etal.’s study revealed that baseline

[

C]MET PET is a prognostic indicator in low-

grade glioma patients, further emphasizing its

importance in survival prediction [49]. They also

determined that [

C]MET uptake plays a crucial

role in determining survival in astrocytoma and

oligodendroglioma patients. Kaschten etal. also

supported the prognostic value of [

C]MET PET

[50]. However, this study involved a heteroge-

neous patient population. Only a single study to

date has challenged the prognostic signicance

of [

C]MET PET, suggesting its lack of mean-

ingful prognostic value [25, 51].

3.2.3 Assessment ofTumor Extent,

Biopsy, andRadiotherapy

Planning

Brain tumors exhibit a heterogeneous distribution

of malignancy grades and necrosis within their

solid mass. Reliance on MRI alone for biopsy

planning can lead to inadequate tissue samples

and inaccurate tumor grading. Consequently,

advanced imaging techniques are crucial to delin-

eate tumor extent more precisely, identify optimal

biopsy targets, and pinpoint areas with heightened

recurrence risk [52]. Numerous studies have dem-

onstrated the incremental value of [

C]MET PET

in biopsy planning.

It is also well-established that CT and MRI

can underestimate the true extent of gliomas in

patients, especially in the context of radiotherapy

planning [53] (Fig. 3.3). This can lead to an

increased risk of radiation necrosis, which can

Fig. 3.3 Patient with a diagnosis of glioblastoma (GBM)

investigated with [

C]MET PET/CT (a), and MRI (b,

T2w-FLAIR; c, Gd-enhanced) before radiotherapy plan-

ning. Note the contoured lesion of the right fronto-parietal

region (SUVmax 7.2; SUVratio 4.8) presenting with cen-

tral necrosis. The white arrows indicating the right frontal

region highlight the presence of a meningioma

3 Positron Emission Tomography fromFDG toAmino Acid Tracers

https://t.me/med1917

occur in up to 24% of patients [54]. [

C]MET

PET has been shown to be superior to other imag-

ing modalities in delineating tumor extent. Pre-

treatment [

C]MET PET appears to identify

areas at highest risk of recurrence, making it a

valuable tool for radiation treatment planning

[52]. [

C]MET PET signicantly improves

tumor volume denition in 88% of low-grade and

78% of high-grade gliomas [55]. Multiple stud-

ies, involving both low-grade and high-grade

tumors, have demonstrated that MET PET is

more accurate than CT or MRI in outlining the

tumor volume [25]. Voges et al. found that the

spatial extent of increased methionine uptake on

[

C]MET PET was larger than on CT/MRI

images in 67% of cases and equal in 33% [56].

3.2.4 [

C]MET PET inBrain Tumor

Recurrence

Challenges arise in distinguishing between recur-

rent tumors and radiation necrosis in post- treatment/

post-irradiation images. CT/MRI patterns can

mimic both conditions, as they both involve disrup-

tion of the blood-brain barrier. To address this issue,

extensive research has been conducted on the use of

[

C]MET PET to differentiate between recurrent

tumors and radiation necrosis (Fig.3.4). Compre-

hensive investigations into the performance of [

MET PET for detecting recurrent gliomas have

yielded valuable insights. Different T/N cut-off

ratios have been employed to establish this associa-

tion. Tripathi etal. [57] utilized a cut-off ratio of

>1.9, achieving high sensitivity and specicity,

along with excellent inter-observer agreement. Ter-

akawa etal. [58] achieved optimal sensitivity and

specicity utilizing a T/N ratio of 1.58 (by

SUVmean). Okamoto etal. [59] observed a statisti-

cally signicant elevation in the T/N ratio in recur-

rent tumors (1.98 ± 0.62) compared to radiation

necrosis (1.27±0.28), demonstrating its diagnostic

value even for small lesions exhibiting a partial vol-

ume effect. Yamane etal. [43] reported a change in

intended management in 45% of patients following

[

C]MET PET evaluation. Van Laere et al. [60]

assessed 30 patients with treated gliomas, demon-

strating positivity in 28 cases. Inter-observer agree-

Fig. 3.4 Patient with relapsed glioblastoma (GBM) of

the right frontal lobe (SUVmax 3.2; SUVratio 1.7) cir-

cumscribed to the posterior portion of the operating cavity

(a, fused axial PET/CT) as shown also by the Gd-enhanced

MRI (b)

A. Piccardo et al.

https://t.me/med1917

ment was 100%, and [

C]MET PET emerged as

the strongest prognostic predictor in a subgroup of

23 patients with astrocytoma. A meta-analysis of 29

studies [61], involving 899 scans, demonstrated that

[

C]MET PET displayed a remarkable level of

diagnostic accuracy (AUC=0.9352) in identifying

recurrent tumors, regardless of glioma grade, study

design, or reference standard. Specicity and sensi-

tivity were reported to be 0.88 (95% CI: 0.85, 0.91)

and 0.85 (95% CI: 0.80, 0.89), respectively, with an

area under the curve (AUC) for the summary

receiver-operating characteristic curve (SROC) of

0.9352. These ndings highlight the effectiveness

of [

C]MET PET in accurately detecting recurrent

gliomas across diverse clinical scenarios [61–64].

3.2.5 [

C]MET inSecondary Brain

Tumors

While contrast-enhanced MRI remains the pre-

ferred imaging modality for diagnosing brain

metastases, limited literature suggests that [

MET PET may play a role in guiding therapy

rather than detection [25]. Terakawa et al. [58]

found that patients with recurrent metastatic

brain tumors exhibited lower T/N ratios com-

pared to those with recurrent gliomas. Grosu

etal. [65] corroborated these ndings, reporting a

mean T/N ratio of 2.6 ± 0.9 in treated glioma

patients and 1.8±0.2in treated metastatic brain

tumor patients. Other studies have investigated

the ability of [

C]MET PET to differentiate

between recurrent metastatic disease and radia-

tion necrosis [65–67]. Similar to gliomas, [

MET PET demonstrated its utility in this distinc-

tion. Yamane et al. achieved a high diagnostic

accuracy for this differentiation in 30 patients

with treated metastatic brain tumors (and 88% in

39 patients with treated glioma) [25, 43].

However, depending on where the metastases

come from, other radiotracers can also be useful.

2-[

F]FDG is useful in high-grade tumors and

tumors with highly increased glucose metabolism,

such as melanoma [68, 69]. In brain metastases

from neuroendocrine tumors, [

Ga]-DOTA-con-

jugated somatostatin receptor targeting peptides

and [

F]DOPA are the radiotracers of choice [70].

In unknown primary tumors presenting as a brain

metastases of unknown primary, 2-[

F]FDG PET

provides information not only of the brain metabo-

lism, but is also useful for searching for the pri-

mary tumor [68, 71, 72]. In summary, given the

high glucose metabolism in the brain, the advan-

tages of [

C]MET over 2-[

F]FDG are clear, thus

it should be the radiotracer of choice if readily

available. Other radiotracers may present advan-

tages depending on the primary tumor. However,

guidelines concur in recommending MRI for the

evaluation of secondary brain tumors, as small

lesions can go undetected in PET. A multidisci-

plinary approach is recommended in the manage-

ment of cancer patients, as has been underlined in

clinical guidelines for many solid tumors [73–79].

Finally, the information supplied by different

radiotracers and different imaging techniques,

including radiomics, may be complementary and

could lead to the development of new biomarkers

with prognostic impact [80–82].

3.2.6 Advantages

andDisadvantages of

[

C]MET Imaging

As previously mentioned, [

C]MET is a radiola-

belled amino acid that has gained considerable

attention for its use in the diagnosis and manage-

ment of brain tumors, primarily gliomas [12,

83–86]. As an amino acid-based radiopharma-

ceutical, it provides unique advantages in brain

tumor imaging, as well as some limitations that

warrant discussion (Table3.3).

In particular, advantages include:

1. Superior target-to-background ratio: Due to

the overexpression of amino acid transporter

systems in brain tumor cells, [

C]MET pro-

vides a superior target-to-background ratio

compared to 2-[

F]FDG [12]. This high con-

trast allows for the accurate detection of

tumor tissue and delineation of tumor

margins.

2. Accurate tumor grading: [

C]MET uptake

correlates with cell proliferative activity,

which can aid in differentiating high-grade

3 Positron Emission Tomography fromFDG toAmino Acid Tracers

https://t.me/med1917

Table 3.3 SWOT (Strength-Weakness-Opportunities-Threats) analysis of [

C]MET for detecting and characterizing

brain tumors

Radiopharmaceutical Strengths Weaknesses Opportunities Threats

Methyl-

C--

methionine

([

C]MET)

– Superior

target-to-

background

ratio

– Accurate

tumor

grading

– Guidance for

stereotactic

biopsy

– Short half-life

(20 min)

– Limited

specicity

– Higher cost

and

complexity

compared to

conventional

imaging

– Development of

new techniques to

overcome short

half-life

– Improved

specicity through

combination with

other imaging

agents

– Competition with

other

radiopharmaceuticals

– Limited accessibility

due to short half-life

and cost

gliomas from histologically benign brain

tumors or non-neoplastic lesions. The uptake

intensity of [

C]MET is also a reliable prog-

nostic factor for tumor aggressiveness.

3. Guidance for stereotactic biopsy: [

C]MET

imaging can be employed to guide stereotac-

tic biopsy, allowing for precise sampling of

tumor tissue, which can be vital for accurate

histopathological diagnosis.

On the other hand, disadvantages of [

C]MET

Imaging comprise:

1. Short half-life: The half-life of

C is approxi-

mately 20 min, which limits the availability

and transport of [

C]MET to PET centers in

close proximity to a cyclotron facility. This

logistical limitation can hinder widespread

adoption of [

C]MET imaging in clinical

practice.

2. Limited specicity: Although [

C]MET has a

high sensitivity for detecting brain tumors, it

can also accumulate in non-tumoral tissues

and inammatory lesions, potentially leading

to false-positive ndings.

3. Cost and complexity: The production and use

of [

C]MET PET imaging are more complex

and expensive than conventional imaging

modalities such as CT and MRI, which may

limit its accessibility, especially in resource-

limited settings.

In summary, PET/CT with [

C]MET is a state of

art technique, well established and widely avail-

able for brain tumors. [

C]MET imaging offers

several advantages in the diagnosis and manage-

ment of brain tumors, including superior target-

to-background ratios, accurate tumor grading,

and guidance for stereotactic biopsy. However,

its use is limited by factors such as its short half-

life, limited specicity, and higher costs com-

pared to conventional imaging modalities. Future

research should focus on addressing these limita-

tions to improve the clinical utility of [

C]MET

in brain tumor imaging. In particular, PET/MR

represents an ideal alternative technique; it com-

bines two modalities that are mandatory in the

diagnostic process of brain tumors and it avoids

exposure to CT-radiation.

3.3 The Role of[

F]FET

inNeuro-Oncology

Magnetic resonance imaging (MRI) is still consid-

ered the rst imaging method for detecting both

primary brain tumors and brain metastases (BM),

due to its soft-tissue contrast, high spatial resolu-

tion, as well as wide availability. Nevertheless,

although new advanced MRI sequences have been

developed (e.g., perfusion- weighted imaging, MR

spectroscopy, and MR-chemical exchange satura-

tion transfer), MRI is not free from weaknesses,

particularly to distinguish between true progres-

sion and treatment- related changes [87, 88]. To

overcome these limitations, PET imaging with

radiolabelled amino acids has received great

impulse in the last years. [

C]C-methyl-

methionine ([

C]-MET), O-(2-[

F]F-uoroethyl)-

-tyrosine ([

F]FET), and 3,4-dihydroxy-6-[

F--phenylalanine ([

F]-DOPA), the three most

widely used amino acid tracers in clinical routine,

A. Piccardo et al.

https://t.me/med1917

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