Emerging PET-radiotracers in cardiovascular, neuro-inflammation, lung and rheumatological diseases: a narrative review

Abstract

Background

Imaging plays a crucial role in the clinical management of patients with inflammatory diseases, both for diagnosis and in evaluating treatment response. 2-deoxy-2-[18F]-fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) is a non-invasive imaging technique that is gaining prominence in the study of various infectious and inflammatory diseases. Advances in PET imaging technology, along with the development of new radiopharmaceuticals, have the potential to enhance the diagnostic accuracy of imaging in the evaluation of inflammation, allowing for the tracking of disease activity through mechanisms distinct from FDG.

Methods

This narrative review aims to explore and discuss the emerging role of new PET/CT radiopharmaceuticals in the field of inflammation taking into account findings from recent studies in this setting.

Results

Preliminary promising findings are available in the literature regarding the potential usefulness of new radiotracers for investigating inflammatory diseases, especially in cardiovascular, neurological, rheumatological and pulmonary fields. In cardiovascular inflammation, different radiopharmaceuticals showed promising roles according to the disease evaluated, but globally the findings are preliminary and heterogeneous. Concerning cardiac sarcoidosis, somatostatin Receptor Subtype 2 (SSTR2)-ligands, translocator protein (TSPO) radiotracers, and hypoxic radiotracers were investigated but until now so strong evidence were available. About vasculitis, SSTR2-ligands and CXCR4 radiotracers showen the most promising findings, especially in the evaluation of treatment response. Regarding atherosclerosis and mycoarditis, we have positive preclinical studies but lack of evidence from a clinical point of view. For neuroinflammation, the available findings on new PET radiotracers are still limited even if TSPO PET seems the most promising due to the ability to image microglial activation. Instead, about lung and rheumatological inflammatory diseases, fibroblast activation protein inhibitors (FAPI) appear to be the most promising radiopharmaceutical, even better than [¹⁸F]FDG, although further solid data are needed.

Conclusions

Emerging PET radiotracers showed promising results in detecting inflammatory diseases in different anatomical sites, but more robust and comprehensive studies are required for their clinical use.

Background

Since the introduction of 2-deoxy-2-[18F]-fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography/computed tomography (PET/CT) into clinical practice, nuclear medicine specialists and healthcare providers have recognized the potential role of this technique for imaging both infectious and inflammatory processes (Abikhzer et al. 2025). Initially, foci of inflammation or infection were considered potential pitfalls of [¹⁸F]FDG PET/CT, leading to false positives findings in oncological patients. However, as experience grew and the application of PET/CT expanded, it became increasingly evident that [¹⁸F]FDG could be effectively used to assess patients with various inflammatory conditions (Casali et al. 2021).

For example, one notable application in this context was the evaluation of fever of unknown origin (FUO), where [¹⁸F]FDG PET/CT demonstrated its ability to significantly influence patient management in a considerable proportion of cases (Hess et al. 2024).

Over the last two decades, the indications for [¹⁸F]FDG PET/CT in inflammatory diseases have broadened, yielding excellent results in several conditions such as large vessel vasculitis (LVV), endocarditis, spinal infections (SI), and systemic and cardiac sarcoidosis (SS/CS) (Abikhzer et al. 2025).

Ongoing clinical studies—especially those employing robust reference standards, multicenter designs, and head-to-head comparisons with other diagnostic modalities—are expected to further refine our understanding and optimize the clinical use of [¹⁸F]FDG PET in inflammatory diseases.

However, [¹⁸F]FDG lacks of high specificity; for example, it is difficult to discriminate between inflammation and infection using [¹⁸F]FDG PET (Kircher et al. 2020). To overcome these limitations and explore alternative metabolic pathways, other PET radiotracers have been developed with promising results.

This narrative review aims to explore and discuss the emerging role of new PET radiopharmaceuticals in the field of inflammation focus especially on cardiovascular inflammatory diseases, neuroinflammation, lung and rheumatological diseases which are according to us the inflammatory conditions with the main interesting findings. These advancements are expected to enhance both the diagnosis and prognostic assessment of patients with inflammatory diseases.

Cardiovascular inflammation

Inflammatory cardiovascular diseases include a wide scenario of diseases including myocarditis, sarcoidosis, vasculitis and atherosclerosis; these conditions are upheld by immune cells-molecular cascades dynamic interactions (Goswami et al. 2021; Malhi et al. 2024; Nakano et al 2001; Szalay et al. 2006). In recent literature radiotracers targeting different pathophysiological aspects of cardiovascular inflammation have been subject of pre-clinical and clinical studies with promising results in the field of diagnosis and treatment monitoring.

Cardiac sarcoidosis

Cardiac sarcoidosis is one of the cardiovascular disease most investigated with new radiotracers, like somatostatin Receptor Subtype 2 (SSTR2)-ligands, translocator protein (TSPO) radiotracers, and hypoxic radiopharmaceuticals. SSTR2 is a G-protein-coupled receptor that is upregulated in activated macrophages, activated lymphocytes, and sarcoid granulomas (Taniyama et al. 2005). Prospective studies have investigated the role of SSTR2-ligands (i.e., [⁶⁸ Ga]DOTATOC) PET/CT in patients with sarcoidosis and suspected cardiac involvement, demonstrating high diagnostic accuracy compared to FDG, high concordance with cardiac magnetic resonance (CMR) imaging (96.1%), and a high target-to-background ratio (Lapa et al. 2016; Gormsen et al. 2016) (Fig. 1). On the contrary, Bravo et al. (Bravo et al. 2021) demonstrated a better sensitivity of FDG PET/CT than [⁶⁸ Ga]DOTATATE PET/CT in detecting cardiac disease and similar performances in the investigation of extracardiac inflammation. One of the potential advantages of SSTR2-ligands than [¹⁸F]FDG is the lack of fasting and/or of specific diet to suppress physiological myocardial uptake. This artefact may strongly reduce the accuracy of [¹⁸F]FDG PET/CT in evaluating heart diseases.

Fig. 1.

A case of false negative 18F-FDG PET/CT scan due to the presence of physiological myocardial uptake and true positive Ga68-DOTANOC PET/CT scan showing a focal increased uptake in the septum(A). A case of false positive 18F-FDG PET/CT with focal uptake in the basal lateral wall of the myocardium, not confirmed at Ga68-DOTANOC PET/CT (B). Part of the figure taken by Gormsen et al. EJNMMI Research (2016) 6:52 (https://doi.org/10.1186/S13550-016-0207-6)

Another class of radiopharmaceuticals investigated were TSPO-targeted PET radiotracers.TSPO is a mitochondrial translocator protein expressed in the outer mitochondrial membrane. These radiotracers have been developed to image microglial activation, which is fundamental in different inflammatory conditions. Moreover, TSPO is also upregulated in several diseases associated with mithocondrial dysfunction, suggesting that TSPO may be a marker of several cardiac diseases (Morin et al. 2016).

Numerous radiotracers have been developed for imaging TSPO with PET, each with different strengths and weaknesses in terms of binding affinity, selectivity, metabolism, and clinical utility (Table 1).

Table 1.

Summary of TSPO radiotracers features

Tracer	Half-life	Polymorphism sensitivity	Pros	Cons
[11C]PK11195	20 min	No	Historic gold standard	Poor SNR, high non-specific binding
[11C]PBR28	20 min	Yes	High brain uptake	Requires genotyping
[18F]FEPPA	110 min	Yes	Longer half-life, good uptake	Polymorphism-sensitive
[11C]DPA-713	20 min	Yes	Good signal, higher selectivity	Genotyping required
[18F]GE-180	110 min	Mild	Better distribution, longer T1/2	Complex pharmacokinetics
[11C]ER176	20 min	Minimal	Low polymorphism sensitivity	Needs on-site cyclotron

SNR: signal to noise ratio

Short representation of the main TSPO radiotracers used for cardiovascular diseases with the main advantages and disadvantages

Thus, several pre-clinical studies investigated the role of TSPO-targeted radiotracers in myocardial injury focusing on post-acute myocardial infarction (AMI) inflammation, myocarditis, sarcoidosis, atherosclerosis and vasculitis (Lucinian et al. 2024). One of this TSPO tracers, [¹⁸F]GE180, was tested in a population of cardiac sarcoidosis who underwent PET/MRI (NCT03561025). The rationale is the fact that sarcoid may induced focal inflammation in myocardium showing high [¹⁸F]GE180 uptake. [¹⁸F]GE180 PET scans will give reliable data about inflammatory sarcoidosis activity in the myocardium. [¹⁸F]GE180 PET is expected to improve diagnostic accuracy compared to [¹⁸F]FDG-PET and/or contrast enhanced MRI.

A potential role of hypoxic radiopharmceuticals, like 18F-fluoromisonidazole.

([¹⁸F]FMISO) and fluoroazomycin arabinoside ([¹⁸F]FAZA), was preliminary investigated with promising results but too premature (Pacella 2022). In a prospective cohort of 10 patient with cardiac sarcoidosis (Furuya et al 2021), [¹⁸F]FMISO and [¹⁸F]FDG were compared. The diagnostic accuracy of these tracers seemed to be very similar both in the investigation of cardiac and extra-cardiac localizations of disease. The big advantage of [¹⁸F]FMISO is the lack of physiological myocardial uptake, causing a no need of special preparations in these patients. But further studies also in multicenter controlled trials are needed to confirm this promising results.

For all these tracers, the main goal should be to reach the diagnosis of cardiac sarcoidosis avoiding invasive procedure, such as biopsy and to help to follow the patients during the management More robust data, especially compared with cardiac MRI are needed.

Large vessel vasculitis (LVV)

A prospective study using SSTR2-PET/CT in 27 patients with LVV observed a significant increase in arterial radiotracer uptake in active disease compared to inactive disease, with activity levels 35% higher than in atherosclerotic lesions. Also the uptake pattern is different between LVV and atherosclerotic inflammation: in atheroclerosis the uptake was lower and patchy rather than circumferential. Follow-up SSTR2 PET imaging after treatment (with corticosteroids and tocilizumab) showed a significant reduction in arterial uptake, correlating with clinical improvement based on the physician’s global assessment score (Corovic et al. 2023). This suggests a potential role for this imaging technique in monitoring therapy response.

A pilot study in humans investigated two different TSPO-related tracers ([¹⁸F]-PBR06 and [¹¹C]-PBR28) in patients with carotid stenosis and vasculitis (Schollhammer et al. 2021) showing positive uptake in in vitro section, but no uptake in all in vivo patients. These results underline the potential limit of this class of radiopharmaceuticals in this scenario (Fig. 2).

Fig. 2.

A n example of TSPO radiotracer, like [18F]-PBR06, in a patient with suspected vasculitis. PET/CT (A, C) scan and angio-CT (B, D) scan demonstrated no uptake on the right carotid atheromatous plaque. Image taken by Schollhammer et al. EJNMMI Res (2021) 11:45 (Doi 101186/s13550-021–00786-7)

Another class of radiopharmaceuticals studied in LVV is chemokine receptor (CXCR4). The chemokine receptor CXCR4 is a G-protein-coupled receptor expressed in immune cells, where it regulates the expression of cell adhesion molecules (Bianchi et al. 2020). [⁶⁸ Ga]labeled pentixafor is a specific ligand for CXCR4, allowing PET imaging. In the setting of vasculitis, an ongoing clinical trial (NCT05604482) will evaluate the uptake of [⁶⁸ Ga]pentixafor in patients with suspected LVV compared to [¹⁸F]FDG. The results could give interesting insights of [⁶⁸ Ga]pentixafor diagnostic value in this specific setting.

Based on the current literature, [⁶⁸ Ga]pentixafor PET/CT proves to be a promising tool for non- invasive detection of myocardial inflammation and vasculitis through the lack of physiological myocardial uptake, its favorable biodistribution and no need for special preparation.

Finally, one retrospective research of 30 LVV patients found broader vessel involvement detected by [¹⁸F]FAPI PET/CT compared to [¹⁸F]FDG, although it remains unclear whether FAPI uptake is caused by vascular inflammation or remodeling phenomena (Zhong et al. 2025).

Concerning LVV, the field of major interest seems to be the treatment response evaluation where, until now, [¹⁸F]FDG presents some limitations and open questions, such as the right time to perform control PET/CT and the potential impact of several therapies (corticosteroids) in the [¹⁸F]FDG distribution.

Atherosclerosis

Atherosclerosis begins with injury or dysfunction of the endothelial lining of blood vessels due to factors like high blood pressure, smoking, or high cholesterol (Gimbrone et al. 2016). This damage increases endothelial permeability, allowing low-density lipoprotein (LDL) cholesterol to enter the vessel wall where it becomes oxidized. Oxidized LDL triggers an inflammatory response by attracting monocytes, which enter the vessel wall and differentiate into macrophages (Wolf et al. 2019). These macrophages engulf oxidized LDL, turning into foam cells that accumulate and form fatty streaks. Persistent inflammation leads to the migration and proliferation of smooth muscle cells, which produce extracellular matrix components, creating a fibrous cap over the plaque. Over time, the plaque grows, narrowing the artery and potentially rupturing, which can cause blood clots and result in heart attacks or strokes (Fan et al. 2022).

PET imaging is able to harness biological processes to characterise high-risk features of atherosclerotic plaque prone to rupture. Current radiotracers are able to track inflammation, microcalcification, hypoxia, and neoangiogenesis within vulnerable plaque. 18 F-fluorodeoxyglucose (18 F-FDG) is the most commonly used radiotracer in vascular studies and is employed as a surrogate marker of plaque inflammation (Sriranjan et al. 2021; Blanchard et al. 2023). Somatostatin2 receptor is expressed in activated macrophages, and therefore, 68 Ga‐DOTATATE represents an attractive molecular probe by which to detect plaque inflammation (Armani et al. 2007). In 2015, a research focus on PET/MRI conducted on patients scheduled for carotid endarterectomy revealed that the uptake of arterial [⁶⁴Cu]DOTATATE was higher in the affected carotid artery than in the unaffected one (Pedersen et al. 2015). The results indicated that the 64Cu-DOTATATE signals in the culprit arteries correlated with increased expression of the CD163 gene, a marker linked to alternatively activated macrophages. Consequently, 68 Ga-DOTATATE may serve as a more specific tracer for investigating inflammation within atherosclerotic plaques. Also a more recent study showed that [⁶⁸ Ga] DOTATATE accurately identified culprit from nonculprit coronary and carotid lesions, as well as stable coronary lesions with high‐risk plaque morphology (Takin et al. 2017). SSTR2-ligands demonstrated better diagnostic performances than FDG.

Also TSPO tracers were shown to be upregulated in activated macrophages in preclinical models (Scarf et al. 2007).This finding was further corroborated by studies performed using explanted human carotid endarterectomy specimens which demonstrated that the TSPO was found on CD68‐positive macrophages (Fujimura et al. 2008; Lomare et al. 2011).

A study done on patients with carotid atherosclerosis showed that patients with symptomatic carotid artery plaque (stroke/TIA) in the preceding 3 months had increased arterial 11CPK11195 uptake compared to asymptomatic individuals (Gaemperli et al. 2012).

Additional research is needed to evaluate the practicality of using these second-generation TPSO radioligands in clinical practice. It also remains uncertain whether differences in receptor binding affinity caused by genetic polymorphisms will limit the broad application of these newer tracers.

Myocarditis

Concerning myocarditis, [¹⁸F]FDG role is limited and the need of alternative radiotracers seems to be necessary (Chaaban et al 2022).

Starting with SSTR2-ligands, two pilot and preliminary clinical studies have shown a correlation between myocardial uptake of SSTR2-ligands at PET and abnormal signals on CMR in myocarditis. Furthermore, a myocardial/blood SUVmax ratio of 2.18 has been reported as a diagnostic threshold during the acute phase of myocarditis (Lapa et al. 2015; Boursier et al. 2023).

Also a potential role of C–C chemokine receptor type 2 (CCR2) radiopharmaceuticals was investigated. CCR2 is predominantly expressed in monocytes, macrophages, and dendritic cells. This receptor regulates monocyte chemotaxis upon binding to its ligand CCL2. The peptide DOTA-ECL1i binds to the CCR2 receptor, enabling PET imaging when labeled with [⁶⁸ Ga] or copper-64 [⁶⁴Cu]. In a mouse model of myocardial inflammation, increased uptake of ⁶⁴Cu-AMD3100 and [⁶⁸ Ga]DOTA-ECL1i was observed in CD36^-/- mice compared to controls, correlating with immune cell infiltration (Cifarelli et al. 2022).

In a similar way, mannose receptor (MR) was studied as potential target. MR is predominantly expressed on macrophages, immature dendritic cells (DCs), and endothelial cells (Paurevic et al. 2024).

In rat model of myocardial inflammation Lee and colleagues described a significant increase of ⁶⁸ Ga-NOTA-MSA uptake in myocardium with myocarditis compared to control. Furthermore, myocardial radiopharmaceutical uptake was downregulated after cyclosporine-A treated rats. Notably, radiopharmaceutical uptake preceded echocardiography abnormalities suggesting the potential role of this molecular probe for early identification of myocarditis and therapy response monitoring (Lee et al 2017).

Neuro-inflammation

Neuroinflammation refers to the complex and dynamic immune response occurring within the central nervous system (CNS) in reaction to various insults, including trauma, infection, autoimmunity, protein aggregation, or toxic injury (Ransohoff et al. 2016). Conversely to systemic inflammation, neuroinflammatory processes are primarily mediated by resident glial cells, most notably microglia and astrocytes, rather than by circulating leukocytes. Microglia, the brain’s resident macrophages, serve as immunological sentinels and rapidly respond to alterations in CNS homeostasis by undergoing morphological and functional transformation. The activation of microglia involves the release of various pro-inflammatory mediators, including interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and reactive oxygen species. Additionally, activated microglia participate in essential functions such as phagocytosis and synaptic remodeling, which are crucial for maintaining neural health and responding to injury or disease (Salter et al. 2017).

Astrocytes, while conventionally regarded as supporting cells, also play a pivotal role in neuroinflammatory signalling. In reaction to microglial activation and central nervous system injury, they may assume a reactive character and either enhance or regulate the inflammatory cascade. The interaction between microglia and astrocytes is bidirectional, characterised by reciprocal signalling that influences the form and magnitude of the inflammatory response.

Acute neuroinflammation can be neuroprotective by clearing debris, enhancing tissue regeneration, and re-establishing homeostasis; nevertheless, persistent or dysregulated inflammation is becoming acknowledged as a significant factor in developing several neurological disorders. Chronic glial activation is associated with neuronal impairment, synaptic loss, and advancing neurodegeneration in conditions like Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis (Amor et al. 2010).

The dual function of neuroinflammation as both a protective and detrimental process highlights its complexity and the necessity for precise control in therapeutic applications. PET is suggested as a promising diagnostic method for the non-invasive examination of neuroinflammatory processes (Owen et al. 2011). While [¹⁸F]FDG remains a standard PET radiotracer in clinical neurology (neurodegenerative diseases), its lack of cellular specificity has prompted the development of new molecular probes to more directly visualise microglial and astrocytic activation in the human brain (Kumlien et al. 2001). Among these, radiotracers targeting the 18-kDa Translocator Protein (TSPO) have dominated the landscape over the past two decades (Papadopoulos et al. 2006).

TSPO is a mitochondrial protein expressed at low levels in the healthy brain but significantly upregulated in response to glial activation, particularly in microglia and reactive astrocytes. Its localisation in activated immune cells, as well as its involvement in mitochondrial function and apoptosis, makes it a suitable target for PET imaging of neuroinflammation (Cumbers et al. 2024). Despite the rationale underlying its potential use in clinical practice, TSPO-guided PET development meets several challenges hampering its accuracy in neuroinflammatory diseases, particularly concerning genetic variability, lack of cellular specificity and commercial issues (Salerno et al. 2024). The most intriguing issue hampering the utilisation of this class of radiopharmaceuticals is that single-nucleotide polymorphism, a variation at a single position in the DNA sequence among individuals. In the context of TSPO-targeted PET imaging, the most clinically significant single-nucleotide polymorphism is rs6971, located in exon 4 of the TSPO gene (Lee et al 2024). This polymorphism results in an amino acid substitution altering the structure of the TSPO binding pocket and markedly affects the affinity of different TSPO-targeting radiotracers. Depending on the presence of the allele variants, individuals can be classified into three binding affinity categories: high-affinity binders (HAB, Ala/Ala), mixed-affinity binders (MAB, Ala/Thr), and low-affinity binders (LAB, Thr/Thr). This classification is crucial because certain radiotracers, such as [¹¹C]PBR28 and [¹⁸F]DPA-714, exhibit significant reductions in binding signal in low-affinity binders, often necessitating their exclusion from studies or statistical corrections (Cumbers et al. 2024). Consequently, prior to imaging, genotype screening is frequently required when using single-nucleotide polymorphism-sensitive tracers.

The first TSPO-targeting radiopharmaceutical developed for clinical imaging was [¹¹C]PK11195. While historically valuable, this compound suffers from a low signal-to-noise ratio, high nonspecific binding, and poor brain permeability. However, a notable advantage is its insensitivity to the rs6971 single-nucleotide polymorphism in the TSPO gene, affecting many other tracers’ binding affinity (Kurumaji et al. 2000; Chauveau et al. 2008). As such, [¹¹C]PK11195 remains the tracer of choice in populations where genotyping is not feasible, or where comparability across TSPO genotypes is critical (Wijesinghe et al. 2025).

To overcome the limitations of [¹¹C]PK11195, several second-generation radiotracers were synthesised, such as [¹¹C]PBR28, [¹¹C]DPA713, and [¹⁸F]DPA-714 (Fujita et al. 2008; Wimberley et al. 2021). These compounds demonstrated improved brain penetration and binding affinity. However, they are severely affected by the rs6971 single-nucleotide polymorphism, which categorises individuals into high-, mixed-, and low-affinity binders. For example, [¹¹C]PBR28 can show an up to 80% difference in binding potential between high- and low-affinity binders, making quantification inconsistent across populations unless genotyping and correction strategies are employed (Wimberley et al. 2021). In this setting, clinical studies using [¹⁸F]DPA-714 have shown promising results in Alzheimer’s disease and multiple sclerosis, where regional uptake correlates with disease activity. Nevertheless, the significant inter-subject variability due to genotype effects remains a critical limitation (Lee et al. 2024).

Third-generation TSPO-targeting radiopharmaceuticals aim to retain the favourable pharmacokinetics of their predecessors while reducing or eliminating single-nucleotide polymorphism sensitivity. [¹¹C]ER176, for instance, exhibits only ~ 10–20% variability across genotypes and has shown promising stability and uptake across various neuroinflammatory conditions (Zanotti-Fregonara et al. 2019; Albert et al. 2017). [¹⁸F]GE180, another third-generation compound, has demonstrated robust binding in multiple sclerosis lesions independent of genotype, with uptake patterns correlating with clinical disease activity (Unterrainer et al. 2018). [¹⁸F]BS224, still under preclinical investigation, shows insensitivity to the rs6971 single-nucleotide polymorphism with low inter-subject variability in experimental models. It has been proposed as a candidate for wider clinical adoption in the future, especially where genotyping is impractical (Chauveau et al. 2025).

TSPO-targeted PET imaging has been applied across a broad spectrum of neurological and neuropsychiatric disorders, reflecting its role as a marker of glial activation and innate immune responses. Studies using [¹⁸F]DPA-714 and [¹¹C]PBR28 have shown correlations between elevated TSPO signal and disease progression or cognitive decline, although results are often confounded by genotype effects.

In multiple sclerosis (MS), TSPO PET has shown high sensitivity to focal and diffuse inflammation. Moreover, it has been beneficial in detecting inflammatory activity in normal-appearing white matter and cortical lesions not evident on conventional MRI. Tracers such as [¹⁸F]GE180 have shown uptake correlating with disease activity in relapsing–remitting MS, even in regions not enhancing with gadolinium (Salerno et al. 2024).

In progressive supranuclear palsy (PSP), increased TSPO binding has been localised to deep grey matter structures, including the pallidum and midbrain. Post-mortem validation confirmed that [¹¹C]PK11195 PET signal correlates with microglial density and CD68 + phagocytic microglial burden, supporting its role in tracking disease progression (Wijesinghe et al. 2025).

TSPO PET has also been explored in psychiatric conditions such as major depressive disorder and schizophrenia. While some studies report increased binding in cortical and subcortical regions, others fail to detect significant differences between patients and controls. The inconsistencies are likely due to the heterogeneity of glial involvement and technical limitations related to tracer affinity variability (Chauveau et al. 2025).

Although TSPO remains the principal molecular target, alternative pathways are being explored. The COX-2-targeting radiotracer [¹¹C]MC1 offers a more specific signal of acute inflammatory processes and has shown promise in both animal models and healthy human volunteers (Yan et al. 2025). Meanwhile, P2X7-targeting tracers such as [¹¹C]SMW139 have shown suboptimal differentiation in multiple sclerosis patients (Bloomfield et al. 2016), limiting their immediate clinical utility.

A comparative summary of key positron-emitting radiotracers employed to study neuroinflammation with regard to generation, target, genetic sensitivity, clinical applications, and findings is presented in Table 2. This overview provides a practical reference to the technical and clinical properties of the most investigated tracers.

Table 2.

Summary of TSPO radiotracers for neuroinflammation imaging

Radiotracer	Generation	Sensitivity to SNP	Pathologies investigated	Key findings
[11C]PK11195	1st	Insensitive (~ 0% variability)	PSP, MS, AD	Still widely used due to insensitivity to rs6971 SNP; low SNR and poor quantification, but correlates with CD68 + microglial burden in post-mortem PSP tissue
[11C]PBR28	2nd	High (~ 80% difference BPND)	AD, ALS	High brain uptake and affinity; BPND variability up to 80% across genotypes. In AD, increased cortical uptake correlates with cognitive decline (MMSE)
[18F]DPA-714	2nd	High (~ 60–80% variability)	MS, AD	Improved SNR compared to PK11195; used in MS and AD; variability in signal requires exclusion or correction for low-affinity binders
[11C]DPA713	2nd	High (~ 70% difference)	AD, Herpes encephalitis	Tenfold higher binding affinity than PK11195 in vitro. More sensitive to TSPO density changes in active neuroinflammation
[18F]GE180	3rd	Moderate (~ 30–50% variability)	MS, Glioblastoma	High uptake in MS active lesions and glioblastoma margins. Signal independent of the rs6971 genotype. TBR up to 6.6 in GBM
[11C]ER176	3rd	Low (~ 10–20% variability)	Various (including depression, AD)	Higher brain distribution volume and stable kinetics. Minimal sensitivity to SNP; suitable for wider populations
[18F]BS224	3rd	Insensitive (~ 0–10% variability)	Preclinical models	SNP-insensitive in vitro and rodent models. In LPS-challenged mice, it correlates with microglial activation; human validation pending
[11C]MC1	Non-TSPO (COX-2)	Not applicable	Neuroinflammation	Binds COX-2 specifically; 25% reduction in neocortical binding with celecoxib blockade; strong correlation with COX-2 mRNA levels
[11C]SMW139	P2X7 (non-TSPO)	Unknown/insufficient data	MS	Binds P2X7 receptor; failed to show clear group separation in MS vs controls; promising in preclinical models, but weak in clinical setting

AD: Alzheimer’s Disease; ALS: Amyotrophic Lateral Sclerosis; BPND: Binding Potential Non-Displaceable; COX-2: Cyclooxygenase-2; GBM: Glioblastoma Multiforme; MMSE: Mini-Mental State Examination; MS: Multiple Sclerosis; P2X7: Purinergic receptor P2X7; PET: Positron Emission Tomography; PSP: Progressive Supranuclear Palsy; SNP: Single-Nucleotide Polymorphism.; SNR: Signal-to-Noise Ratio; TBR: Tumour-to-Background Ratio; TSPO: Translocator Protein 18 kDa

In conclusion, TSPO-targeting radiopharmaceuticals remain central to the in vivo imaging of neuroinflammation, with ongoing advancements in third-generation ligands mitigating previous issues related to genotype sensitivity. Nevertheless, the lack of cellular and functional specificity (e.g., distinguishing microglial phenotypes) underscores the need for complementary approaches targeting alternative molecules/targets such as enzymes (COX-2, MAO-B) or receptors (CSF1R). Future radiopharmaceuticals must strive for cell-type selectivity, single-nucleotide polymorphism-independence, and dynamic responsiveness to inflammatory states to fully realise PET’s potential in neuroimmunology.

Inflammatory lung diseases

Concerning inflammatory lung diseases, FAPI, labeled with either [18F] or [68 Ga], are emerging as promising radiopharmaceuticals. FAP is a type II transmembrane serine protease belonging to the dipeptidyl peptidase 4 family. It is highly overexpressed on the membranes of cancer-associated fibroblasts (CAFs) in approximately 90% of epithelial-derived cancers (Fitzgerald et al., 2020). However, FAP may also be present in cases of tissue damage, remodeling, or chronic inflammation, which can occur in benign conditions as well (Treglia et al., 2023; Albano et al., 2024). In contrast, healthy tissues typically exhibit low FAP expression. FAPI tracers offer several advantages over [¹⁸F]FDG, including higher tumor-to-background ratios (TBR), rapid renal clearance, and favorable tracer kinetics. These benefits result in a shorter interval between injection and imaging, with no dependence on blood glucose levels or patient rest. First, Röhrich et al. (Rohrich et al. 2022) performed FAPI PET/CT in 15 patients with fibrotic interstitial lung disease (fILD) and suspected lung cancer (LC) as a potential complication. PET/CT scans were conducted at different time points after radiotracer administration (10, 60, and 180 min), with three patients also undergoing a dynamic study over 40 min instead of an early static scan (Fig. 3). In both conditions (fILD and LC), increased radiotracer uptake was observed, with SUVmax and SUVmean values higher in LC than in fILD. TBRs remained relatively stable in fILD but tended to increase over time in LC. Instead, significant differences in the time-activity curves during dynamic studies for LC and fILD were observed. fILD lesions showed an early peak followed by a slow reduction in signal intensity, whereas LC lesions exhibited a late peak and a subsequent gradual washout phase. These preliminary results suggest that FAPI PET/CT could be a promising imaging tool for studying fILD and suspected LC, with dynamic imaging showing the greatest potential for differentiating between benign and malignant lesions.

Fig. 3.

MIP 68 Ga-FAPI PET images at different time points (A) in a patient diagnosed with interstitial lung disease (ILD) and non–small cell lung carcinoma (indicated by a red arrow). The images revealed intense ^68 Ga-FAPI uptake in fibrotic areas of the right middle lobe (blue arrow) and moderate uptake in the right lower lobe (yellow arrow). Figure taken by Rohrich et al. Eur J Nucl Med Mol Imaging. 2024 May;51(6):1605–1611. https://doi.org/10.2967/Jnumed.121.261925

An increased FAPI uptake in inflammatory lung diseases was demonstrated by two other studies (Yang et al. 2023; Qiao et al. 2024). Yang et al. conducted both in vitro and in vivo studies to explore whether the intensity of FAP expression could serve as a potential marker for estimating or quantifying activated fibroblasts in ILD. Through immunohistochemical analysis, they found that FAP expression was significantly upregulated in the early stages of interstitial diseases, particularly those characterized by lung fibroblast activation. These findings were supported by PET/CT scans, where the uptake—expressed as SUV—was significantly correlated with a decline in pulmonary function in patients with ILD. Also in the other study (Qiao et al. 2024), despite increased FAPI uptake in inflammatory lesions, lung oncological diseases presented significantly higher uptake, expressed as SUVmax, SUVmean, and TBR (p < 0.001 in all cases). Among the inflammatory findings, those with the highest uptake were infected bronchiectasis, followed by post-obstructive pneumonia and pneumonia.

This difference is potentially due to the ability of FAPI to concentrate especially in areas of fibrosis, as demonstrated in a study based on eight patients affected by idiopathic pulmonary fibrosis (Mori et al. 2024). This study found that fibrotic changes in the pulmonary parenchyma showed a significant increase in FAPI uptake in both visual and semi-quantitative analyses. Additionally, FAPI uptake was strongly correlated with lung density, as measured by Hounsfield units, and clinical parameters such as forced vital capacity.

Beyond diagnostic purposes, FAPI PET/CT also showed promising results in treatment monitoring and response evaluation. In a population with systemic sclerosis-associated ILD (Bergmann et al., 2021), FAPI uptake was higher in patients with extensive disease compared to those with limited disease, in patients with previous ILD progression compared to those with stable disease, and in patients with high EUSTAR activity scores compared to low scores. Furthermore, baseline FAPI uptake was associated with the risk of disease progression, independent of the extent of lung involvement seen on high-resolution CT scans or the forced vital capacity at baseline. When monitoring treatment responses, changes in FAPI uptake on sequential scans were consistent with radiological and clinical responses in patients treated with nintedanib. A recent study (Bahtouee et al., 2025) compared FAPI with a gamma-emitter tracer (99mTc-MIBI) characterized by the lipophilic and cationic nature, that allows it to passively diffuse across cell membranes and accumulate in mitochondria-rich tissues. In this study the combination of FAPI and 99mTc-MIBI findings demonstrated an additive role in evaluating ILD-related fibrosis and inflammatory processes.

In conclusions, the use of FAP-targeted imaging radiotracers shows great promise beyond oncology, particularly for inflammatory and fibrotic lung diseases. This expands the clinical applications of FAPI PET/CT from primarily cancer imaging to non-malignant conditions involving tissue remodeling and fibrosis. Compared to [^18F]FDG, FAPI tracers offer higher tumor-to-background ratios, rapid clearance, and no dependency on patient blood glucose levels or resting state. These advantages facilitate quicker imaging protocols and potentially better lesion detection specificity.

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Rheumatological diseases

IgG4-related disease

Also for the investigation of IgG4-related disease (IgG4-RD), FAPI was investigated with controversial findings. In a head-to-head comparison study with [¹⁸F]FDG (Luo et al. 2021), FAPI showed a higher detection rate in detecting disease in the pancreas, liver, biliary ducts, and head&neck organs (like lacrimal and salivary glands). This superiority was particularly evident in the head-and-neck region due to the low background uptake of FAPI and subsequent better TBR than [¹⁸F]FDG that may be physiologically present in the extraocular muscles and salivary glands.

On the other hand, the accuracy in the evaluation of nodal disease was weak for FAPI: all [¹⁸F]FDG -avid lymph nodes resulted FAPI-negative. The reason was the lack of storiform fibrosis (common in extranodal IgG4-related diseases) in nodal localization.

The limitation about the role of FAPI in this disease was underlined also by a second study (Schmidkonz et al. 2020) where combination of FAPI and [¹⁸F]FDG findings helped to discriminate between inflammatory and not inflammatory fibrosis. Particularly, IgG4-RD foci characterized by inflammation were [¹⁸F]FDG positive and FAPI negative, while foci of fibrosis were the opposite (FDG negative and FAPI positive). They also found that [¹⁸F]FDG uptake was very responsive to anti-inflammatory therapy, FAPI was not.

These results may significantly impact the management of certain immune-mediated diseases, such as IgG4-related disease, where subtypes characterized by fibrosis may require tailored approaches to control disease progression. For instance, these cases may benefit more from specific antifibrotic agents rather than broad-spectrum anti-inflammatory treatments like steroids.

However, more robust data are needed to confirm or controvert the effective role of FAPI PET in IgG4-RD.

Inflammatory arthritis

From a theoretical point of view, FAPI could be a reliable, reproducible and accurate biomarker for the evaluation of disease activity in arthritis, like rheumatoid arthritis (RA), because activated fibroblast-like synoviocyte cells have a fundamental role in the pathogenesis of RA. In favor of this argument, several studies demonstrated a superiority of FAPI PET than [¹⁸F]FDG in the detection of RA disease. In a prospective study based upon 20 patients, the authors (Luo et al. 2023) compared the detection rate of these two radiotracers in assessing joint disease activity. FAPI PET recognized more pathological joints than [¹⁸F]FDG and average SUVmax was significantly higher. Moreover, there was a significant correlation between FAPI uptake and C-reactive protein levels.

Concerning treatment response evaluation in RA, Pan et al. studied 19 patients with a baseline ⁶⁸ Ga-FAPI and [¹⁸F]FDG PET/CT before starting antirheumatic drugs followed by a control after 3 and 6 months (Pan et al. 2024). Baseline PET features were useful to predict treatment response. Patients with high total synovitis uptake and metabolic synovitis volumes with FAPI, and high number of PET positive joints were significantly higher in patients with good treatment response.

Also in preclinical study (Zhang et al. 2023), this association between severity of inflammation in arthritis and FAPI uptake was demonstrated, such as the potential usefulness to predict treatment response.

A recent preclinical study hypothesized a potential usefulness of CXCR4-targeted PET imaging in RA demonstrating a positive impact in monitoring disease activity and evaluating treatment efficacy (Han et al. 2025). However, future research are shareable to test in the clinical scenario these preliminary findings.

Beyond RA, one research about FAPI and psoriatic arthritis was available. A recent research (Corte et al. 2025) investigated a prospective cohort study using ⁶⁸ Ga-FAPI-04 PET/CT to investigate whether the distribution of tracer uptake correlates with clinical and ultrasound findings, and whether the presence of articular tracer uptake in patients with psoriasis is associated with the risk to develop psoriatic arthritis. A total of 36 patients with biopsy-proven or clinical-confirmed psoriasis and arthralgia were prospectively recruited. ⁶⁸ Ga-FAPI-04 uptake was detected in 318 joints (7.9%) and 369 entheses (7.3%) in 29 (80.6%) patients. A significant positive correlation was found between ⁶⁸ Ga-FAPI-04 PET/CT uptake intensity and the tender joint count as well as the tender entheses count, though no correlation was observed with ultrasound findings. Eleven of 13 patients were diagnosed psoriatic arthritis, confirmed by both clinical and imaging evidence of the condition. Thus, patients with high synovial and entheseal FAPI uptake had a significantly higher risk of developing arthritis. Moreover, a positive FAPI-PET/CT predicts progression to arthritis independently of ultrasound findings. These findings suggest that the earliest signs in the joints and entheses of patients with psoriasis transitioning to arthritis are hallmarked by the activation of tissue-resident mesenchymal cells and can be detected by FAPI PET.

In conclusion, concerning inflammatory arthritis and IgG4-related disease, it seems too premature to suggest the best emerging radiotracer.

Conclusions

This review has certain limitations. Firstly, the narrative and non-systematic nature of the approach may have resulted in the omission of some references on the topics discussed. Additionally, the selection of the most significant studies from the literature was somewhat arbitrary.

Despite promising preliminary findings in other tracers, [¹⁸F]FDG remains the best tracer for imaging inflammatory diseases. However, some novel molecular radiopharmaceuticals that map alternative pathways are under development and may overcome its limitations.

[⁶⁸ Ga]-labeled PET radiopharmaceuticals have the potential to play a role in the diagnosis of inflammatory diseases due to their uptake mechanisms and the high target-to-background ratio. On the other hand, [¹⁸F]-labeled radiotracers offer advantages related to production and scheduling.

Regarding cardiovascular inflammation, different radiotraecers classes were investigated with very heterogeneous results and related to the disease considered. For sarcoidosis,

TSPO and hypoxia- tracers showed positive preliminary positive findings especially in cases of negative or doubtful [18F]FDG. About LVV, [⁶⁸ Ga]pentixafor seems to be most promising emerging tracer available.

Instead, concerning and myocarditis, we have positive preclinical studies but lack of evidence from a clinical point of view.

About neuroinflammation, TSPO-targeting radiopharmaceuticals remain central to the in vivo imaging, with ongoing advancements in third-generation ligands mitigating previous issues related to genotype sensitivity.

FAPI-based radiotracers, in contrast, have shown a positive impact in the study of interstitial lung disease and rheumatological diseases.

Head-to-head comparison studies are crucial to determining the best alternative to [¹⁸F]FDG.

More robust and comprehensive studies are required for the use of novel PET radiotracers in inflammatory diseases.

Author contributions

DA, AR, LL proposed ideas about the work and the concepts of the study. CR and AR performed the systematic review and data extraction. GT performed the meta-analysis. DA, AG and GT prepared the first draft of the manuscript. All authors reviewed the manuscript. All authors have read the final manuscript and approved the version to be published.

Declarations

Ethical approval

Ethical approval and consent to participate. This is a review article; therefore, ethical approval is not applicable.

Competing interests

The other authors declare no conflict of interest.