Molecular Brain Tumor Imaging Beyond [¹⁸F]FDG: Somatostatin Receptor PET, Amino Acid PET, and Emerging Applications—From the AJR Special Series on Molecular Imaging

Abstract

PET using established and emerging molecularly targeted radiotracers has become integral to the evaluation and management of brain tumors, providing biologic information that complements conventional MRI to improve tumor characterization, treatment planning, and response assessment across a broad spectrum of neurooncologic diseases. Although [¹⁸F]FDG PET remains widely available, the technique is limited by high physiologic grey matter uptake. Somatostatin receptor (SSTR)-targeted PET, including DOTATATE PET, has greatly impacted meningioma evaluation through high tumor-to-background contrast, aiding radiotherapy planning and response assessment, along with patient selection for peptide receptor radionuclide therapy. SSTR-targeted PET has also been applied for paragangliomas, esthesioneuroblastomas, and other SSTR-positive tumors. Amino acid PET further improves the evaluation of gliomas and brain metastases, particularly for distinguishing tumor progression from treatment-related change. Emerging radiotracers targeting hormone receptors, hypoxia, tumor neovasculature, and the tumor microenvironment continue to expand the biologic information available from PET, while theranostic applications increasingly integrate molecular imaging with targeted therapy. This Special Series Review summarizes the current clinical roles of [¹⁸F]FDG, SSTR-targeted agents, amino acid tracers, and emerging radiotracers in the PET evaluation of brain tumors, highlighting the tracers’ strengths and limitations. The article also explores evolving applications that are further integrating targeted PET into precision neurooncology.

Introduction

Although MRI provides excellent anatomic delineation for the diagnosis and treatment planning of brain tumors, critical limitations remain. In particular, the differentiation of treatment-related changes from viable tumor after surgery, radiation therapy, or systemic treatment presents a common clinical challenge. Advanced MRI techniques including arterial spin labeling, dynamic susceptibility contrast perfusion imaging, and dynamic contrast-enhanced perfusion imaging can aid this distinction [1]. However, the available techniques have inherent technical limitations; for example, the accuracy of dynamic susceptibility contrast perfusion imaging may be reduced by susceptibility artifacts from intralesional hemorrhage [1, 2]. Additionally, their performance varies across institutions because of differences in acquisition and postprocessing methods. PET complements MRI by characterizing tumor biology rather than anatomy or hemodynamics, providing information that is often unavailable from conventional structural or advanced MRI techniques. Yet, while [¹⁸F]FDG established the role of PET in oncologic imaging, the application of [¹⁸F]FDG PET in the brain is constrained by high physiologic cortical uptake.

These limitations have driven the development and clinical adoption of molecularly targeted PET radiotracers that interrogate tumor-specific biologic pathways. Targeted PET provides molecular information that complements conventional MRI to improve diagnosis, tumor characterization, treatment planning, and response assessment across a broad spectrum of neurooncologic diseases. Accordingly, molecular imaging using such agents has become integral in the evaluation and management of brain tumors, helping to resolve common clinical dilemmas and support more precise, individualized care compared to conventional MRI alone.

This Special Series Review summarizes the current clinical roles of [¹⁸F]FDG, somatostatin receptor (SSTR)-targeted tracers, amino acid tracers, and emerging radiotracers in the PET evaluation of brain tumors, highlighting the tracers’ strengths and limitations while emphasizing clinical applications in meningiomas, gliomas, and metastatic disease. The article also explores evolving applications that are serving to further integrate targeted PET into precision neurooncology.

Established Radiopharmaceuticals

[¹⁸F]FDG PET

Background, indications, and protocol—

[¹⁸F]FDG PET has historically been used in the posttreatment evaluation of brain tumors to differentiate viable neoplasm from treatment-related changes such as radiation necrosis.

[¹⁸F]FDG is an ¹⁸F-labeled glucose analog that enters cells via glucose transporters [3]. Most malignant processes demonstrate increased glycolytic activity, known as the Warburg effect, and [¹⁸F]FDG is therefore preferentially taken up by tumor cells. However, an increase in [¹⁸F]FDG uptake also occurs in areas of active inflammation [3].

Per published multisociety practice guidelines, a static image acquisition with 10–20 minute duration should be obtained at least 45 minutes after injection [4]. Dual-time-point [¹⁸F]FDG PET, including delayed imaging 4–5 hours after injection, may improve differentiation between viable tumor and radiation necrosis in neurooncologic settings, although applicability in the realworld setting is limited due to time constraints [5].

Interpretation—

In the posttreatment setting of brain tumors, focally increased [¹⁸F]FDG avidity may indicate viable tumor, whereas absent or low avidity is more supportive of radiation sequelae (Fig. 1). However, SUV thresholds to distinguish posttreatment change from viable tumor are lacking, and interpretation relies on comparison with background cortical and white matter avidity. Interpretation should integrate conventional MRI findings, perfusion MRI characteristics, and interval imaging when available.

Figure 1.

65-year-old man undergoing follow-up after radiation therapy for meningioma. (A) Axial DWI from posttreatment MRI shows new restricted diffusion in corpus callosum (arrow). (B) Axial [¹⁸F]FDG PET image shows corresponding photopenia (arrow), which was favored to reflect radiation necrosis. PET rainbow color scale set to SUV_max range of 0 to 15.

Limitations and pitfalls—

The utility of [¹⁸F]FDG PET is limited by high physiologic uptake in cortical and deep gray matter, resulting in reduced tumor-to-background contrast and partial volume effects. Although higher uptake is generally associated with higher-grade gliomas, reliable SUV thresholds to distinguish tumor grade are lacking, and overall diagnostic performance remains modest [6]. Differentiation of posttreatment change from viable tumor is limited due to the potential for inflammation-related [¹⁸F]FDG avidity and partial volume averaging effects with physiologically avid cortex [3]. Less commonly, luxury perfusion phenomena, as encountered in the setting of subacute infarct, may mimic viable tumor [7]. While [¹⁸F]FDG remains widely available, these limitations highlight the need for improved biomarkers in neurooncologic PET in clinical practice.

SSTR PET

Radiolabeled somatostatin analogs, including DOTATATE, bind to SSTR2 and enable high tumor-to-background contrast because of minimal physiologic uptake in normal brain parenchyma. Physiologic avidity is largely confined to the pituitary.

Meningioma: background and indications—

Meningiomas are the most common primary intracranial neoplasm in adults and demonstrate near-universal overexpression of SSTR2. This overexpression provides the biologic basis for SSTR-targeted PET, which has greatly impacted meningioma management [8, 9].

Contrast-enhanced MRI remains central to meningioma management from initial diagnosis to posttreatment surveillance. Characteristic MRI features of meningiomas include a broad-based dural attachment, avid and relatively homogeneous contrast enhancement, and reactive thickening of adjacent dura (dural tail). Meningiomas also show restricted diffusion on DWI and commonly have associated hyperostosis that is better delineated on CT. The inability of conventional MRI to reliably predict tumor grade remains a key limitation considering that clinical outcomes for meningiomas worsen substantially with increasing WHO grade, including markedly higher recurrence rates for grade 2 and 3 lesions [9].

SSTR PET complements MRI by improving lesion detection, defining disease extent, and increasing diagnostic confidence in challenging clinical scenarios. For example, SSTR PET can help distinguish meningioma from schwannoma, with the latter typically demonstrating absent or minimal SSTR avidity [10]. An important application of SSTR PET is patient selection for peptide receptor radionuclide therapy (PRRT), representing the first clinically established theranostic paradigm in neurooncology [11]. Emerging evidence also supports the technique’s role in treatment response assessment, including monitoring response to systemic therapies such as bevacizumab [12]. Theranostic applications are discussed in detail in a later section.

Joint practice guidelines from the European Association of Nuclear Medicine (EANM), European Association of Neuro-Oncology (EANO), Response Assessment in Neuro-Oncology (RANO), and Society of Nuclear Medicine and Molecular Imaging (SNMMI) (hereafter, the joint EANM/EANO/RANO/SNMMI practice guidelines) recommend use of SSTR PET for patients with known or suspected meningioma, including for initial diagnosis, disease monitoring, and theranostic use with PRRT [11]. SSTR PET is also used for the evaluation of patients with known systemic malignancy who present with a symptomatic or incidental extra-axial mass; in this scenario, differentiation of meningioma and dural metastasis is challenging. Intense SSTR tracer avidity strongly supports meningioma (Fig. 2), whereas absent or low avidity raises concern for alternate causes depending on the primary tumor.

Figure 2:

83-year-old woman undergoing surveillance after breast cancer treatment. (A) Axial postcontrast T1-weighted MR image shows enhancing extra-axial mass (arrow), indeterminate for meningioma versus other dural-based neoplasm in setting of known malignancy. (B) Axial fused image from subsequent DOTATATE PET/MRI shows moderate DOTATATE avidity (arrow), compatible with meningioma. PET rainbow color scale set to SUV_max range of 0 to 15.

SSTR PET is also particularly useful for meningioma evaluation in anatomically complex regions such as the cavernous sinus and optic nerve sheath, where conventional imaging findings may be nonspecific. Tracer avidity can increase confidence in the diagnosis of meningioma and help exclude mimics such as lymphoma, vascular lesions, inflammatory processes, or schwannoma (Figs. 3,4) [10]. Multiple case reports have similarly demonstrated the utility of SSTR PET in optic nerve sheath meningioma, although larger studies are needed to better define the test’s diagnostic performance and optimal clinical role in this setting [13, 14].

Figure 3:

74-year-old woman who presented with elevated blood pressure and chest pain, prompting brain MRI. (A) Axial postcontrast T1-weighted MR image shows enhancing lesion in left cavernous sinus (arrow). (B) Axial image from DOTATATE PET shows corresponding intense DOTATATE avidity (arrow). Lesion was resected, yielding diagnosis of meningioma. PET rainbow color scale set to SUV_max range of 0 to 15.

Figure 4:

59-year-old woman presenting with double vision, dizziness, and headaches (A) Axial postcontrast T1-weighted MR image shows enhancing lesion in right cavernous sinus (arrow). (B) Axial image from DOTATATE PET shows lack of corresponding DOTATATE avidity (arrow). Pituitary gland shows physiologic avidity (SUV_max, 20.9) Lesion was resected, yielding diagnosis of cavernous sinus lymphoma. PET rainbow color scale set to SUV_max range of 0 to 15.

Another important application is the delineation of transosseous tumor extension. Conventional imaging may not reliably distinguish reactive hyperostosis from osseous tumor invasion. SSTR PET enables more accurate definition of intraosseous disease extent, with a reported sensitivity of 99% compared with 54% for contrast-enhanced MRI, and maintained high specificity (Fig. 5) [15]. Given that osseous involvement is associated with increased risk of recurrence, accurate delineation has direct implications for surgical and radiation planning [16–18].

Figure 5.

75-year-old woman with progressive dizziness for approximately 1 year. (A) Axial postcontrast T1-weighted MR image shows expansile heterogeneously hypoenhancing calvarial mass along left frontoparietal convexity (arrow). (B) Axial CT image shows densely sclerotic appearance of lesion (arrow), suggesting diagnosis of intraosseous meningioma. (C) Axial image from DOTATATE PET/CT shows corresponding intense circumscribed DOTATATE avidity (arrow), confirming suspected diagnosis of meningioma and delineating disease extent. PET rainbow color scale set to SUV_max range of 0 to 15.

SSTR PET also provides a promising biomarker for treatment response assessment following stereotactic radiosurgery or stereotactic body radiotherapy (Fig. 6). In a prospective study, DOTATATE PET demonstrated marked reductions in SUV and SUV ratio (SUVR) normalized to the superior sagittal sinus (SSS) after radiation therapy despite minimal change in lesion size on conventional MRI. Greater reductions in DOTATATE uptake were associated with improved progression-free survival, supporting the complementary role of SSTR PET as a biomarker of biologic treatment response beyond conventional anatomic imaging [16].

Figure 6:

36-year-old woman undergoing follow-up after subtotal resection for CNS WHO grade 2 meningioma. (A) Coronal postcontrast T1-weighted image from posttreatment DOTATATE PET/MRI shows residual tumor (arrow). (B) Corresponding coronal fused PET/MR image better delineates extent of residual tumor (arrow) and thus provides more accurate guidance for subsequent stereotactic radiosurgery (SRS). (C) Coronal postcontrast T1-weighted image from DOTATATE PET/MRI performed after SRS shows minimal change in appearance of residual tumor (arrow). (D) Corresponding coronal fused PET/MR image shows marked decrease in DOTATATE avidity (arrow), compatible with treatment response. PET rainbow color scale set to SUV_max range of 0 to 15.

Gross total resection remains the primary treatment for meningiomas; however, recurrence remains common in higher-grade tumors. Following surgery, integrated SSTR PET/MRI improves assessment of residual disease and postoperative gross total resection status, enabling active surveillance in selected patients with WHO grade 2 meningioma [19]. In patients undergoing radiation therapy, SSTR PET improves target delineation and helps distinguish recurrent tumor from posttreatment change when MRI findings are equivocal (Fig. 6) [16].

These clinical benefits are supported by a cost-effectiveness analysis that concluded that SSTR PET is economically favorable in selected patients with treated meningioma [20].

Other brain tumors: background and indications—

In addition to meningiomas, SSTR-targeted PET has shown clinical utility in other SSTR2-expressing intracranial and skull base tumors including paragangliomas, pituitary neuroendocrine tumors (PitNETs), neuroblastoma, and esthesioneuroblastoma [21, 22]. Paragangliomas show extremely high SSTR2 expression, resulting in intense tracer uptake and excellent lesion conspicuity. SSTR PET improves diagnostic confidence when conventional imaging is indeterminate and may facilitate theranostic evaluation.

PitNETs are a common benign intracranial tumor with heterogeneous SSTR2 expression. Interpretation is complicated by high physiologic avidity of the normal pituitary, which shows one of the highest baseline levels of SSTR PET avidity in the body [23]. As a result, macroadenomas and pitNETs with extrasellar extension are more readily delineated on PET than are microadenomas (Fig. 7) [24]. Quantitative approaches using both absolute SUV and normalized metrics (e.g., SUVR, typically referenced to the SSS) have been proposed to improve lesion characterization and reproducibility [25]. SSTR PET may be most useful for pitNET evaluation in clinical scenarios where conventional MRI findings may be equivocal, including differentiation of residual tumor from posttreatment change and evaluation of invasive or atypical lesions. SSTR2 expression varies across PitNET subtypes, potentially influencing both imaging appearance and response to targeted therapies [26].

Figure 7.

19-year-old man presenting with biochemical and clinical recurrence after resection of large sellar thyrotropic pituitary neuroendocrine tumor (pitNET). (A) Axial postcontrast T1-weighted MR image shows mass in left cavernous sinus (arrow), invading left mesial temporal lobe. (B) Axial image from DOTATATE PET/MRI (arrow) shows intense circumscribed DOTATATE avidity (arrow), compatible with recurrent pitNET. PET rainbow color scale set to SUV_max range of 0 to 15.

Esthesioneuroblastoma is a rare sinonasal neuroectodermal malignancy with a propensity for delayed locoregional recurrence. Esthesioneuroblastoma shows high SSTR2 expression, providing a molecular theranostic target [22]. Given its nonspecific clinical presentation and broad imaging differential, SSTR PET can improve diagnostic confidence and assist in staging. In addition, SSTR PET has demonstrated utility in evaluating treatment response and detecting recurrent disease, particularly in anatomically complex regions of the skull base and in the setting of intracranial and systemic metastases.

Protocols—

SSTR PET images are typically acquired 40–60 minutes after IV tracer injection, although earlier acquisition may also be appropriate and allows dynamic PET analysis [11, 27]. A study using [⁶⁸Ga]Ga-DOTATOC demonstrated equivalent lesion detection with imaging performed approximately 15 minutes after injection compared with conventional 60-minute acquisition[28], supporting protocol flexibility in clinical practice.

Interpretation—

Interpretation of SSTR PET relies on integration of both qualitative and quantitative findings. Immunohistochemical studies demonstrating near-universal SSTR2 expression in meningiomas underpin the high sensitivity of SSTR-targeted imaging [29]. DOTATATE PET has shown excellent diagnostic accuracy for meningiomas [25]; comparable performance has been reported for other somatostatin analogs including DOTATOC, DOTANOC, and [¹⁸F]SiTATE [30–34]. Both absolute SUV and SUVR normalized to the SSS have been proposed for lesion characterization [15, 25, 34]. In one study, an SUVR normalized to the SSS of 3.2 provided the highest overall diagnostic accuracy, whereas an absolute SUV threshold of 4.7 was the most specific[25]. The SUVR normalized to the SSS may also offer improved reproducibility across patients and scanners. These thresholds should be interpreted in conjunction with conventional MRI findings, surgical history, and interval imaging.

Limitations and pitfalls—

False-positives have been documented in case reports, including rare cases of tumors that are not typically SSTR2-expressing [61] and of nonneoplastic pathologies [35]. SSTR2-negative meningioma has been rarely described and represent an important limitation [36]. Interpretation can also be challenging when the SUV_max or SUVR in a given lesion approaches proposed diagnostic thresholds. In these situations, lesion morphology, conventional MRI appearance, and clinical context should take precedence over quantitative metrics alone. Additional multicenter validation is needed to determine the generalizability of quantitative thresholds across scanners and institutions. Furthermore, quantitative diagnostic thresholds have not been established for SSTR-positive intracranial neoplasms other than meningioma, limiting interpretation primarily to qualitative assessment.

Amino Acid PET

Background—

Amino acid PET leverages upregulation of amino acid transporters in neoplastic cells and a relative lack of physiologic avidity in normal brain parenchyma to achieve an improved tumor-to-background ratio (TBR) compared to [¹⁸F]FDG PET. Several amino acid PET tracers have demonstrated high diagnostic accuracy for differentiating viable tumor from treatment-related change and have become essential components of contemporary neurooncologic imaging [37].

[¹⁸F]fluciclovine, a synthetic amino acid analog targeting LAT1/ASCT2 transporters, is FDA-approved for biochemical recurrence in prostate cancer and has emerged as an appealing option for off-label neurooncologic imaging because of its commercial availability [38, 39]. Other amino acid analog PET tracers include [¹⁸F]FDOPA (currently FDA-approved for the evaluation of Parkinsonian syndromes), [¹¹C]methionine (currently used in investigational settings only), and [¹⁸F]fluoroethyl-L-tyrosine ([¹⁸F]FET, undergoing FDA review as of this writing). Although limited regulatory approval and tracer availability have restricted widespread adoption of amino acid PET in the United States, growing clinical experience and incorporation into multidisciplinary practice guidelines support the technique’s expanding role in neurooncology [37, 40].

Indications and protocols—

A guideline from the RANO PET working group and EANO recommends the use of amino acid PET in patients with gliomas for tumor delineation, biopsy guidance, and treatment response assessment, recognizing improved evaluation compared with MRI for distinguishing tumor from treatment-related changes (Figs. 8–9) [37].

Figure 8.

63-year-old man undergoing follow-up after maximal safe resection and chemoradiation for glioblastoma. (A) Axial T1-weighted postcontrast image from posttreatment MRI shows heterogeneous enhancement along margins of right temporoparietal resection cavity (arrow and arrowheads). (B) Axial image from [18F]fluciclovine PET/MRI shows corresponding focal moderate avidity along posterior margin of cavity (arrow) with SUV_max of 5.8, concerning for viable tumor; lower-level avidity is present along anterior and medial cavity margin (arrowheads, SUV_max 3.6–3.9). Subsequent resection confirmed recurrent infiltrative glioblastoma corresponding to region of highest [¹⁸F]fluciclovine avidity. PET rainbow color scale set to SUV_max range of 0 to 7.

Figure 9.

69-year-old man undergoing follow-up after administration of radiation and temozolomide for treatment of right thalamic glioblastoma. (A) Axial T1-weighted postcontrast image from posttreatment MRI shows no significant enhancement of right thalamic lesion (arrow). (B) Axial T1-weighted postcontrast image from subsequent follow-up MRI shows new enhancing lesion along trigone of right lateral ventricle (arrow). Dynamic contrast-enhanced perfusion imaging did not show elevation in plasma volume, and DWI showed central reduced diffusion in lesion (not shown). These findings favored treatment-related change rather than tumor progression. (C) Axial [¹⁸F]fluciclovine PET image shows low-level avidity below threshold for viable tumor (SUV_max, 1.2), consistent with radiation necrosis. PET rainbow color scale set to SUV_max range of 0 to 7.

In patients with brain metastases, amino acid PET is similarly recommended for distinguishing recurrent tumor from radiation-related changes following stereotactic radiosurgery and other forms of radiation therapy (Figs. 10–11) [40]. Prospective data from the PURSUE study established histopathologically validated interpretation criteria and demonstrated good overall diagnostic performance, with semiquantitative approaches such as measurement of SUV_max showing robust accuracy [41]. In a recent meta-analysis, amino acid PET had pooled sensitivity of 82% and pooled specificity of 84% for differentiating recurrent metastases from treatment-related change [42]. In that meta-analysis, additional potential benefits of amino acid PET in the posttreatment setting included fewer invasive procedures and decreased overtreatment for treatment-related changes [42].

Figure 10.

45-year-old woman with breast cancer undergoing follow-up after surgery and radiation for treatment of brain metastasis. (A) Axial T1-weighted postcontrast image from surveillance MRI examination shows mass-like enhancement in right posterior frontal lobe in peri-Rolandic region (arrow). (B) Axial [¹⁸F]FDG PET image shows corresponding radiotracer avidity (arrow) (SUV_max, 14.3); this avidity is indeterminate for viable neoplasm versus radiation sequela given its linear cortically based morphology. (C) Axial plasma volume parametric map derived from dynamic contrast-enhanced perfusion sequence performed during short interval follow-up [18F] fluciclovine PET/MRI shows corresponding elevation in plasma volume (arrow), increasing concern for viable neoplasm. (D) Concurrent axial fused PET/MR image shows corresponding [¹⁸F]fluciclovine avidity (SUV_max, 8.2), compatible with viable neoplasm (arrow). PET rainbow color scale set to SUV_max range of 0 to 15 in (B) and to SUV_max range of 0 to 7 in (D).

Figure 11.

62-year-old man with lung adenocarcinoma undergoing follow-up 1 year after stereotactic radiosurgery for treatment of brain metastasis. (A) Axial T1-weighted postcontrast image from posttreatment MRI shows enhancing lesion in right thalamus (arrow), indeterminate for recurrent tumor. MRI also showed mildly elevated relative cerebral blood volume along the posteromedial margin of lesion (not shown). MRI findings raised concern for viable tumor. (B) Axial [¹⁸F] fluciclovine PET image shows corresponding low-level avidity (SUV_max, 2.4), favoring predominantly treatment-related change. Diagnosis of treatment-related change was supported by stable finding on subsequent clinical and MRI follow-up (not shown). PET rainbow color scale set to SUV_max range of 0 to 7.

Interpretation—

Interpretation of amino acid PET is tracer-specific and should integrate visual assessment with quantitative metrics when appropriate. Absolute SUV and TBR thresholds differ across radiotracers and clinical indications, and PET findings should always be interpreted alongside conventional MRI, advanced MRI techniques, and interval imaging.

In a prospective study of glioblastoma with histopathologic confirmation, [¹⁸F]fluciclovine PET differentiated tumor progression from pseudoprogression with 90% sensitivity and 83% specificity at an SUV_max cutoff of 4.66 [39]. A subsequent multicenter clinical validation study demonstrated a similar SUV_max cutoff of 5.7, albeit was limited by retrospective design and protocol heterogeneity among institutions [38]. In an additional study, [¹⁸F]fluciclovine avidity was higher for high-grade than for low-grade gliomas [43].

For [¹⁸F]FET and [¹⁸F]FDOPA, the PET RANO 1.0 criteria recommend a threshold mean TBR of 1.6 for differentiating tumor progression from treatment-related changes in gliomas [44]; similar thresholds have been determined for patients with brain metastases [40]. Amino acid PET may identify small foci of viable tumor that are occult on conventional MRI, although sensitivity decreases for subcentimeter lesions [45].

Absolute and relative SUV thresholds vary across tracers and require further validation. Clinical judgement, in conjunction with findings’ temporal evolution as well as conventional, perfusion, and spectroscopic MRI findings, should be considered in clinical practice [46].

Emerging evidence suggests that amino acid PET provides information beyond lesion detection. In a prospective study that integrated dynamic [¹⁸F]fluciclovine PET with perfusion MRI and transcriptomic profiling, imaging-derived metrics showed correlations with underlying tumor metabolic programs and overall survival [47]. The findings link tracer avidity to biologic pathways such as amino acid transport and autophagy and support a role for amino acid PET in biomarker-driven patient stratification.

Limitations and pitfalls—

Although amino acid PET has greater specificity than [¹⁸F]FDG PET, increased amino acid PET uptake is not specific to gliomas or brain metastases. In case reports, [¹⁸F]fluciclovine avidity has been reported in meningiomas [48], while [¹⁸F]FET avidity has been reported in inflammatory conditions such as neurosarcoidosis [49].

Sensitivity is reduced for small lesions, particularly those measuring less than 1 cm. In one study, approximately one-third of brain metastases smaller than 1 cm were [¹⁸F]FET-negative [50]. False-negative examinations may also occur in tumors with relatively low amino acid transporter expression or altered metabolic phenotypes favoring glucose utilization.

Finally, quantitative interpretation should be individualized. Most published thresholds have been derived from patient cohorts with glioblastoma and may not generalize to lower-grade gliomas or other tumor types [43]. Amino acid transporter expression varies across molecular subtypes and may evolve during treatment, resulting in heterogeneous tracer uptake within and between tumors. Consequently, low tracer uptake does not exclude viable tumor, and PET findings should always be interpreted in conjunction with MRI findings and the broader clinical context. For example, approximately 20–30% of IDH-mutant CNS WHO grade 2 gliomas demonstrate little or no amino acid uptake [51].

Other Emerging Tracers

Beyond the clinically established applications of [¹⁸F]FDG, SSTR-targeted agents, and amino acid tracers, several additional molecular radiotracers are emerging for selected neurooncologic indications. These agents exploit distinct biologic pathways and may further promote the role of PET in diagnosis, treatment selection, and response assessment. These tracers are currently investigational in most neurooncologic settings, and the available evidence remains limited, Nonetheless, the tracers illustrate the continued expansion of brain tumor PET beyond glucose metabolism toward imaging of specific tumor receptors, metabolic pathways, and components of the tumor microenvironment.

[¹⁸F]FES

[¹⁸F]fluoroestradiol PET provides a complementary receptor-targeted approach in patients with brain metastases from estrogen receptor-positive breast cancer. By directly imaging estrogen receptor expression, [¹⁸F]FES PET can differentiate viable tumor from treatment-related change when MRI and [¹⁸F]FDG PET are both limited by nonspecific findings (Fig. 12). Early studies indicated encouraging diagnostic performance of [¹⁸F]FES PET [52, 53]. In a recent prospective study using a dynamic brain [¹⁸F]FES PET protocol, the acquisition timing significantly impacted lesion detectability, with optimal performance occurring 60–75 minutes after injection [54]; the findings highlight the importance of protocol standardization for neurooncologic applications.

Figure 12.

63-year-old woman with hormone-receptor positive breast cancer undergoing follow-up after resection and radiation therapy for treatment of left cerebellar brain metastasis. (A) Coronal T1-weighted postcontrast MR image shows nodular enhancement along margins of left cerebellar resection cavity (arrow), concerning for progression. (B) Axial image from [¹⁸F] fluoroestradiol PET shows corresponding moderate radiotracer uptake along superior cavity margin (arrow) (SUV_max, 5.5), consistent with estrogen receptor-positive viable tumor. PET rainbow color scale set to SUV_max range of 0 to 5.

PSMA

PSMA is a type 2 transmembrane glycoprotein receptor that is expressed on the neovasculature of a variety of solid tumors, including glioblastoma [55] and brain metastases [56]. Early clinical studies have demonstrated favorable tumor-to-background contrast because of minimal physiologic brain avidity for PSMA[55, 57, 58]. However, experience is limited, and challenges remain in distinguishing recurrent tumor from treatment-related change.

FAPI

Fibroblast activation protein inhibitor (FAPI) PET targets cancer-associated fibroblasts within the tumor microenvironment and has emerged as a promising oncologic imaging agent. Early studies have reported excellent lesion conspicuity and high TBR [59–63], relating to the brain’s minimal physiologic FAPI uptake. Such findings indicate potential utility of FAPI PET for brain metastases and high-grade gliomas, although available evidence remains limited.

FMISO

[¹⁸F]fluoromisonidazole ([¹⁸F]FMISO) PET uses the intracellular trapping of nitroimidazole compounds within hypoxic tissue to enable noninvasive assessment of tumor hypoxia. [¹⁸F]FMISO PET has been investigated primarily in high-grade gliomas as a biomarker of prognosis and treatment response, reflecting the contribution of hypoxia to radioresistance, treatment failure, and aggressive tumor biology. Early clinical studies have demonstrated associations of increased [¹⁸F]FMISO uptake with shorter survival and regions of future tumor progression [64, 65], suggesting potential utility of [¹⁸F]FMISO PET for treatment planning and response assessment. However, clinical adoption remains limited, and further prospective validation is needed before routine implementation.

Theranostics

SSTR-targeted imaging provides a direct bridge from diagnosis to therapy, establishing the first clinically mature theranostic paradigm in neurooncology whereby the same molecular target is used for both lesion detection and treatment. This approach is most developed for meningiomas, for which the high and relatively homogeneous SSTR2 expression enables both sensitive imaging with DOTATATE PET and patient selection for PRRT.

PRRT using [¹⁷⁷Lu]Lu-DOTATATE and, less commonly, [⁹⁰Y]DOTATOC, has demonstrated clinical activity in patients with recurrent or progressive meningiomas who are not candidates for further surgery or radiation. The joint EANM/EANO/RANO/SNMMI practice guidelines [11] recognize PRRT as a treatment option in selected patients with SSTR2-positive meningiomas, particularly in the salvage setting. Across retrospective series and early prospective cohorts, PRRT has been associated with disease stabilization in a substantial proportion of patients while having acceptable toxicity profiles [66–69]. However, objective response rates remain modest, and optimal patient selection criteria continue to evolve.

Prospective trials are ongoing to better define the role of PRRT in meningioma management. For example, the LUMEN-1 trial in Europe [70] and the MOMENTUM-1 trial in the United States [71] are both evaluating [¹⁷⁷Lu]Lu-DOTATATE in patients with recurrent or refractory meningioma across WHO grades, using progression-free survival and disease control as key endpoints. SSTR-targeted PET serves as the primary imaging biomarker for patient selection and treatment monitoring in both trials, reinforcing the central role of molecular imaging in guiding therapy.

Beyond meningioma, the application of PRRT to other primary brain tumors remains investigational. A prospective study suggested that SSTR-targeted therapy may be feasible in selected patients [72], although the heterogeneity of SSTR2 expression in gliomas represents a key limitation [73]. These preliminary observations highlight a potential avenue for future study but require validation in larger cohorts.

Beyond systemic therapy, theranostic principles may also facilitate intraoperative tumor localization, and gamma-probe guided surgery may improve delineation of tumor margins in selected patients [74].

While SSTR2 currently represents the most mature therapeutic target, early clinical experience with amino acid transporter-targeted radionuclide therapy, including [¹³¹I]iodofalan [75], suggests that theranostic strategies may ultimately expand beyond SSTR-targeted approaches to additional molecular pathways in neurooncology.

Conclusion

The expanding availability of targeted PET radiotracers has transformed brain tumor imaging beyond glucose metabolism, enabling noninvasive assessment of receptor expression, amino acid transport, hypoxia, and other biologic processes that complement conventional MRI. These techniques improve diagnostic confidence, refine treatment planning, and aid posttreatment assessment across a broad spectrum of primary and metastatic brain tumors.

Beyond diagnosis, targeted PET is increasingly informing precision neurooncology through biomarker-guided treatment selection, response assessment, and theranostic applications. As additional radiotracers and targeted therapies continue to emerge, PET will play an increasingly important role in individualized brain tumor management by linking tumor biology with clinical decision-making.

Table 1:

Summary of PET radiotracers used for brain tumor evaluation

Tracer	Mechanism	Neurooncologic Uses	Strengths	Limitations	Status
[18F]FDG	Glucose analog; reflects intracellular glycolytic activity	Brain tumor evaluation	Widely available, high clinical familiarity	Physiologic cortical avidity results in poor target-to-background ratio; inflammatory conditions may be avid	FDA-approved
[18F]fluciclovine	Synthetic amino acid analog transported by amino acid transporters	GBM, metastasis	Higher target-to-background ratio compared with [18F]FDG	Less established than [18F]FDG; limited data beyond GBM and brain metastases	FDA-approved for suspected recurrent prostate cancer; neurooncology use is off-label
DOTATATE	Somatostatin receptor ligand, primarily targets SSTR2 expression	Meningioma detection; pituitary neuroendocrine tumor (adenoma) detection	High contrast between meningioma and background; useful for transosseous tumor delineation; useful for differentiating residual or recurrent tumor from posttreament change and for differentiating meningioma from metastasis	Limited familiarity	FDA-approved for neuroendocrine tumors; neurooncology use is off-label
[18F]FET	Amino acid tracer transported intracellularly via LAT1 amino acid transporter	Glioma delineation; recurrence vs treatment effect	Extensive clinical use and validation in Europe; low uptake in normal brain regions	Not FDA-approved; limited U.S. availability and clinical experience	Not FDA-approved; established use in Europe
[18F]FES	Estradiol analog that binds ER-positive tumor sites	Metastasis evaluation in ER-positive breast cancer	Noninvasive whole-body ER assessment	Not useful for assessing HER2 or PR status	FDA-approved to detect ER-positive lesions, including as adjunct to biopsy
[18F]FDOPA	Radiolabeled analog of L-DOPA that is transported into tumor via amino acid transporters; also reflects dopaminergic pathway biology in striatum	Glioma delineation; recurrence vs treatment effect; Parkinsonism	Lower background uptake than [18F]FDG	Basal ganglia physiologic uptake may obscure interpretation of deep gray matter lesions	FDA-approved for suspected Parkinsonian syndromes; neurooncology use is off-label
[11C]MET	Radiolabeled methionine amino acid tracer reflecting amino acid transport and protein synthesis	Glioma delineation; recurrence vs treatment effect	Lower background uptake than FDG	Short half-life of carbon-11 requires onsite cyclotron	Investigational for neurooncology; available under expanded access protocols at certain sites
[18F]FAPI	Fibroblast activation protein inhibitor targeting FAP expression in cancer-associated fibroblasts and tumor stroma	Emerging use in the evaluation for primary and metastatic brain tumors	Low uptake in normal brain parenchyma	Less established than [18F]FDG	Investigational
[18F]FMISO	Nitroimidazole tracer that accumulates in hypoxic cells	High-grade glioma evaluation	Noninvasive assessment of tumor hypoxia	Limited clinical experience and validation	Investigational
PSMA	Ligand targeting PSMA expression, present in tumor neovasculature in some nonprostate tumors.	Imaging of tumor neovasculature in gliomas and metastases; assessment for prostate cancer brain metastases	Alternate approach relative to other tracers	Limited neurooncologic evidence	FDA-approved for prostate cancer indications; neurooncology use is off-label

Highlights.

• Targeted PET complements MRI by noninvasively characterizing tumor biology in patients with brain tumors.

• SSTR-targeted PET has become an established tool for meningioma diagnosis, treatment planning, and theranostic patient selection.

• Amino acid PET and emerging targeted PET radiotracers are expanding precision neurooncology through improved response assessment and biologically informed treatment planning.