Nonmalignant FAPI Uptake on PET/CT: From Diagnostic Pitfall to Fibroblast Biology Insights

Methodology

A narrative literature review was performed using PubMed, Scopus, and Web of Science databases up to January 2026. Searches were conducted using combinations of keywords including “fibroblast activation protein inhibitor,” “FAPI,” “PET/CT,” “nonmalignant uptake,” “fibrosis,” “inflammation,” and “benign lesions.” Original articles, retrospective and prospective studies, case reports, and relevant reviews addressing nonmalignant FAPI uptake were considered.

Pathophysiological basis of FAPI uptake beyond cancer

The upregulation of FAP reflects a conserved molecular program triggered by tissue injury and fibrotic remodelling, rather than a cancer-specific biology.^[10]

Under homeostatic conditions, fibroblasts maintain a quiescent state with minimal FAP expression. Following tissue injury, ischemic stress, or chronic inflammation, these cells are activated through complex molecular signalling pathways, primarily driven by profibrotic cytokines.^[11] Transforming growth factor-β1 (TGF-β1) emerges as the dominant molecular regulator of fibroblast activation, promoting transcriptional programs that augment extracellular matrix (ECM) synthesis, fibroblast proliferation, and protease-mediated remodelling.^[12] Furthermore, platelet-derived growth factor (PDGF) and pro-inflammatory cytokines act synergistically to augment fibroblast recruitment and activation within the injured tissue niche.^[1] This biological mechanism explains why FAPI PET reflects active fibroblast-driven tissue remodelling rather than tumour metabolism, distinguishing it fundamentally from FDG PET.

In their activated state, fibroblasts orchestrate dynamic ECM remodelling through increased synthesis of structural matrix constituents such as collagen types I and III, fibronectin, and proteoglycans, together with the expression of enzymes that regulate matrix turnover and tissue architecture.^[5]

A critical stage in this cellular transition is the acquisition of the myofibroblast phenotype, defined by de novo α-smooth muscle actin (α-SMA) expression and extensive reorganisation of the cytoskeletal framework.^[13] This lineage commitment is driven by sustained TGF-β1 signalling in concert with mechanical signalling pathways activated by progressive extracellular matrix stiffening.^[12] Sustained cytokine signalling and mechanical stress progressively drive the transition from physiological tissue repair toward pathological fibrotic remodelling.^[11] Myofibroblasts produce powerful contractile forces that reshape the ECM and promote scar maturation, accompanied by markedly increased expression of FAP.^[14] FAPI-based molecular imaging demonstrates that radiotracer uptake parallels myofibroblast density in fibrotic tissue, with strong spatial concordance between α-SMA expression and FAPI accumulation.^[15] Thus, FAPI PET preferentially identifies active fibrogenesis rather than established scar tissue, enabling early detection of fibrotic activity and dynamic remodelling in non-oncologic diseases.^[16]

Clinical spectrum of nonmalignant FAPI uptake

Nonmalignant FAPI uptake represents a spectrum of fibroblast-driven processes encountered in inflammatory, fibrotic, physiological, post-interventional, and benign stromal-rich conditions. Despite their clinical diversity, these entities share a common underlying mechanism of activated fibroblasts and extracellular matrix remodelling, explaining their appearance on FAPI PET/CT. However, substantial overlap with malignancy, together with heterogeneous and predominantly small-scale evidence, limits diagnostic specificity and necessitates careful, context-based interpretation. These diverse uptake patterns, summarised in Table 1, highlight the importance of careful interpretation in clinical practice.

Inflammatory Conditions

FAP is not exclusive to cancer stroma; it is also expressed by activated fibroblasts/myofibroblasts during tissue remodelling, including inflammation that evolves into fibrosis (or has a fibro-inflammatory phenotype).^[17]

Infectious diseases

Pulmonary infection may show focal or diffuse FAPI uptake, sometimes mimicking metastases.^[3] Uptake intensity varies by subtype: infectious (non-organising) pneumonia typically shows low activity (median SUVmax 2.2; range 1.5–3.7).^[18] In contrast, organising pneumonia can exhibit markedly higher uptake (SUVmax 11.7–12.2) ^[19,20], reflecting prominent fibroblast proliferation.

Dual-tracer data from Kailin Qiao et al., comparing AlFNOTA-FAPI-04 with FDG PET/CT, showed significantly lower FAPI uptake in inflammatory lesions than in malignancies, supporting its role in differentiating infection from tumour.^[21] In radiation-induced lung injury, although acute radiation pneumonitis is typically FDG-avid, preclinical data suggest FAPI uptake may be less affected, potentially improving early post-radiotherapy assessment.^[22]

Tuberculosis (TB) lesions may be distinctly FAPI-avid because granulomatous inflammation often coexists with fibroblast activation and scarring. Active TB may therefore mimic lung cancer with metastatic lymphadenopathy on FAPI PET/CT.^[23] However, old calcified TB scars or small inflammatory nodes may show minimal or no FAPI uptake despite being FDG-avid, suggesting FAPI reflects fibroblast-driven remodelling more than acute inflammation.^[24] Overall, inflammatory lesions may demonstrate a wide spectrum of uptake intensity, occasionally overlapping with malignant lesions, indicating that SUV thresholds alone are insufficient to distinguish benign from malignant processes.

Autoimmune disorders

Autoimmune thyroiditis is one of the most consistently reported inflammatory conditions with documented SUV values.^[25] A study of over 800 patients found incidental diffuse FAPI uptake in the thyroid in about 5% of cases, with 27 of 28 analysed subjects diagnosed with chronic thyroiditis, mostly Hashimoto’s (96%). Mean SUVmax was 5.75 ± 5.45, showing no correlation with thyroid-stimulating hormone and thyroid peroxidase antibody.^[25] This uptake is linked to FAP expression in fibrosis and inflammation in autoimmune processes.

In rheumatologic disease, particularly rheumatoid arthritis (RA), FAPI uptake reflects activation of fibroblast-like synoviocytes and synovial remodelling.^[26] In an original prospective PET study using an ¹⁸F-labeled FAPI tracer, RA-affected joints showed higher uptake than controls (median SUVmax 3.5 vs 2.3). Importantly, uptake increased with disease activity: median SUVmax 5.2 (high activity) vs 3.5 (moderate) vs 2.8 (low).^[27] Studies confirm its feasibility for monitoring therapy, with higher baseline uptake predicting better outcomes.^[28]

IgG4-related disease

IgG4-related disease (IgG4-RD) is a prototypical fibroinflammatory disorder characterised by storiform fibrosis and abundant activated fibroblasts, making FAPI uptake biologically plausible.^[29] Several prospective cohorts and case reports have demonstrated higher uptake in IgG4-RD lesions on FAPI PET/CT compared with FDG, particularly in fibrotic organs such as the pancreas, submandibular glands, and bile ducts. In some series, FAPI imaging identified up to 50% more involved organs than FDG, with generally higher SUV values, supporting its potential role in diagnosis, staging, and treatment monitoring.^[29]

Yaping Luo et al. described a case with IgG4-RD in whom FAPI PET/CT showed higher uptake than FDG in most lesions and uniquely detected submandibular gland involvement.^[29] After steroid therapy, FDG activity decreased, while FAPI uptake persisted in the pancreas and submandibular glands, supporting a potential role for FAPI in both diagnosis and follow-up.^[30] Data are promising but remain limited to small cohorts with incomplete histopathologic validation.

Vasculitis

Vascular wall uptake represents another emerging nonmalignant indication. FAPI can distinguish between low-grade arterial plaque uptake (SUVmax approximately 1.6– 3.0) and vasculitis-related uptake, which may demonstrate substantially higher values.^[3] In large-vessel vasculitis, the reported SUVmax value is approximately 6.4.^[31] These values may equal or even exceed those observed with FDG PET in certain cases.^[31]

Vascular FAPI uptake may also occur outside classic vasculitic processes. Emerging clinical observations suggest that thrombotic lesions may demonstrate tracer accumulation during the phase of thrombus organisation, likely reflecting perithrombotic fibroblast proliferation and extracellular matrix remodelling. This pattern may mimic nodal or soft-tissue metastatic disease when seen adjacent to vessels and should therefore be interpreted in the proper anatomic context.^[6] Evidence remains limited and heterogeneous, requiring further prospective validation.

Inflammatory pancreatic and biliary tract patterns

Inflammatory uptake within the pancreas and biliary system deserves particular caution, as diffuse pancreatic FAPI expression may reflect non-malignant fibro-inflammatory processes rather than diffuse tumour infiltration. Clinical observations have shown that cholangitis and related pancreaticobiliary inflammation may generate intense or mosaic tracer uptake patterns, potentially mimicking multifocal disease unless interpreted in conjunction with clinical findings, laboratory parameters, and complementary imaging.^[32] Findings are largely observational, and differentiation from malignancy remains challenging. This pattern represents an important diagnostic pitfall, particularly in patients undergoing staging for pancreatic or hepatobiliary malignancies.

Fibrotic disorders

Fibrotic disorders are among the most biologically reasonable benign indications for FAPI PET because FAP is overexpressed on activated fibroblasts and myofibroblasts during active tissue remodelling. Accordingly, FAPI uptake reflects ongoing fibroblast-driven fibrogenesis rather than static scar tissue, and is typically more prominent in active fibrosis than in inactive scarring^.[33] These observations suggest that FAPI PET may serve not only as a diagnostic imaging modality but also as a molecular biomarker of active fibrogenesis in systemic fibrotic diseases.

Post-myocardial infarction remodelling

Following acute myocardial infarction, the infarcted and peri-infarct myocardium undergo sequential inflammation and fibroblast activation. Early fibroblast activation detected by FAPI PET has been shown to carry prognostic significance.^[17] Diekmann et al. showed that FAPI-positive myocardial regions may exceed infarct size on MRI or perfusion defects on SPECT. This likely reflects activated fibroblasts in the peri-infarct border zone rather than necrosis alone. Importantly, FAPI uptake volume predicts later left ventricular dysfunction and adverse remodelling.^[34]

More broadly, cardiac fibroblasts, comprising approximately 15–20% of adult myocardial cells, become activated after injury, contributing to replacement and reactive fibrosis.^[34] Preclinical models have shown that FAPI uptake correlates with early stages of cardiac fibrosis and pressure overload– induced remodelling, including associations with right ventricular overload and secondary congestive liver fibrosis in heart failure models.^[35]

Interstitial lung disease and pulmonary fibrosis

Interstitial lung disease (ILD) provides a particularly strong use case because fibroblast activation is central to progressive fibrotic phenotypes. FAPI PET/CT detects elevated uptake in fibrotic lung areas of ILD patients, including those with idiopathic inflammatory myopathies, systemic sclerosis, and idiopathic pulmonary fibrosis.^[36] Kastriot Kastrati et al. showed that in idiopathic inflammatory myopathies-ILD, baseline pulmonary FAPI uptake was higher than in non-ILD controls and linked to inflammation and fibrosis extent.^[37]

A recent study aimed to confirm that FAPI PET uptake reflects true fibroblast activation in advanced ILD by correlating imaging findings with tissue FAP expression. It demonstrated a positive correlation between tracer uptake and histopathologic FAP expression, supporting FAPI PET as a potential imaging biomarker of fibrosis in ILD.^[38] These observations further support the concept that FAPI PET may serve as a molecular biomarker of active fibrogenesis rather than merely reflecting structural fibrosis.

Liver cirrhosis

FAP is expressed on activated fibroblasts and hepatic stellate cells in fibrotic liver, with minimal expression in normal liver. FAP-expressing cells cluster at fibrotic septa and interact with macrophages, amplifying profibrogenic signalling and matrix deposition.^[39] Cirrhosis shows high FAPI uptake because of the true fibrosis signal. A dedicated case series described FAPI uptake patterns in cirrhosis, highlighting that cirrhotic parenchyma itself can demonstrate uptake.^[40]

A pilot study evaluated FAPI-04 PET/CT as a noninvasive method for assessing liver fibrosis. Hepatic FAPI uptake correlated with fibrosis severity and showed comparable performance to established tools such as FibroScan and FIB-4.^[41] These findings suggest that FAPI PET may serve as a molecular imaging biomarker of active liver fibrogenesis. This highlights the potential role of FAPI PET as a noninvasive tool for assessing dynamic fibrotic activity rather than static architectural liver damage.

Renal fibrosis

FAPI shows promise for non-invasive detection and assessment of renal fibrosis. Studies demonstrate high uptake of FAPI-04 in fibrotic kidneys, correlating with fibrosis severity. SUVmax values rose from 3.92±1.50 (mild) to 7.67±2.23 (severe).^[42] FAP expression increases in activated fibroblasts during the progression of renal fibrosis in chronic kidney disease models.

This imaging may complement biopsy by enabling noninvasive visualisation of bilateral renal involvement, potentially aiding disease assessment and monitoring. Ongoing trials are evaluating variants such as AlF-NOTAFAPI-04 to assess inflammation and fibrosis in kidney disease (NCT05752097).

A major clinical contribution is a study by Shuyi Yu et al., which demonstrates the feasibility of FAPI PET/CT for assessing renal tubulointerstitial fibrosis in lupus nephritis, with correlations between renal uptake and measures of chronicity and fibrosis.^[43]

Benign stromal-rich lesions

Many benign tumours contain abundant fibroblast-rich stroma and extracellular matrix components, which may result in intense FAPI uptake and potentially mimic malignancy during oncologic PET imaging.^[44] The broader spectrum of nonmalignant FAPI uptake patterns is summarised in Table 1.

Mechanistic basis

Many benign tumours are characterised by abundant fibrous stroma, reactive fibroblasts, or collagen-rich matrices, creating a microenvironment similar, at least partially, to desmoplastic malignancies.^[45] This uptake reflects stromal biology, not malignancy, and intensity varies with fibroblast activation and matrix remodelling, creating important diagnostic pitfalls.

Reported benign tumours with FAPI uptake

Despite their diverse histologies, these lesions share a common imaging mechanism: fibroblast-rich stroma, extracellular matrix remodelling, or reparative fibrosis, all of which may produce FAPI avidity independent of malignancy. Benign FAPI-avid lesions can be broadly grouped into three categories.

Fibroblastic or spindle-cell stromal lesions include solitary fibrous tumours (SFTs), schwannomas, fibrous dysplasia, and keloids. SFTs demonstrate high FAP expression in collagen-rich spindle-cell stroma, with reported intense uptake (SUVmax 8–15) and higher lesion detection rates compared with FDG in selected series.^[46,47] Schwannomas may also show marked uptake, occasionally mimicking malignancy on PET imaging.^[48] Fibrous dysplasia can demonstrate intense tracer accumulation due to active fibroblast proliferation, sometimes resembling metastatic bone disease.^[49,50] Keloids exhibit avid uptake related to ongoing fibroblast activation and collagen deposition, with uptake often most pronounced at lesion margins.^[51]

Hormone-responsive fibrous lesions, such as uterine leiomyomas and breast fibroadenomas, demonstrate uptake related to hormonally driven stromal proliferation. Leiomyomas may show substantially higher uptake than normal uterine tissue (SUVmax up to ~13), and benign metastasising leiomyomas may exhibit strong FAPI avidity despite low FDG uptake.^[52,53] Similarly, fibroadenomas may demonstrate increased uptake due to their fibroepithelial stromal composition, occasionally mimicking malignancy on staging studies.^[54]

Benign lesions with reactive stromal remodelling include hepatic haemangiomas, myositis ossificans, pancreatic pseudocysts, and thyroid adenomas. In these conditions, uptake reflects fibrosis or reparative processes rather than neoplasia. Haemangiomas may demonstrate unexpectedly high FAPI uptake, sometimes exceeding that of coexisting malignancies.^[55,56] Myositis ossificans shows increased uptake during early fibroproliferative phases and may mimic soft-tissue or osseous metastases without careful CT correlation.^[57] [Fig 1]. Pancreatic pseudocysts associated with chronic inflammation may show variable uptake (SUVmax up to ~21.8), posing diagnostic challenges in differentiating from malignancy.^[44] Thyroid adenomas, particularly follicular types, may also demonstrate intense uptake due to fibrous proliferation and can mimic malignant thyroid nodules.^[58]

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Fig 1: FAPI PET/CT in myositis ossificans. (A) Axial CT (soft tissue) and sagittal views (white arrows). (B) Fused PET/CT images show intense tracer uptake (white arrowheads). (C) CT (bone window) demonstrates heterotopic ossification around the bilateral hip joints with a characteristic zonal pattern (peripheral mature bone and central immature component) (black arrows). Marked FAPI avidity is noted (SUVmax 18.3). Adapted from^[57] under CC BY 4.0. FAPI: Fibroblast activation protein inhibitor; CT: Computed tomography; PET/CT: Positron emission tomography/computed tomography

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Clinical experience from tertiary oncology centres confirms that degenerative musculoskeletal changes, post-interventional sites, and benign stromal lesions are among the most frequent causes of nonmalignant FAPI uptake in routine practice. In a retrospective study, numerous incidental findings, most commonly degenerative joint disease, muscular activity, and benign tumours such as leiomyomas, were identified, underscoring the importance of recognising these patterns to avoid misinterpretation [Fig 2].^[7] Overall, evidence for many benign stromal-rich lesions remains largely case-based, with substantial overlap in uptake intensity with malignancy, limiting the reliability of quantitative differentiation.

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Fig 2: Common nonmalignant FAPI uptake patterns and pitfalls. (A) MIP image showing multiple incidental uptake sites (arrows and dotted arrow). (B) Mild uptake in the right axillary fold (dotted arrow). (C) Diffuse uptake in benign prostatic hyperplasia (curved arrow). (D) Physiologic uptake at the anorectal junction (asterisk). (E) Bilateral knee uptake related to degenerative changes (arrows). Adapted from ^[7] under CC BY 4.0. FAPI: Fibroblast activation protein inhibitor; MIP: Maximum intensity projection

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Physiologic and post-interventional uptake

While benign stromal lesions represent structured fibroblast- rich entities, physiological and post-interventional uptake patterns reflect transient or reactive fibroblast activation processes. Recognising physiological and post-interventional uptake patterns is important for accurate interpretation of FAPI PET in oncologic imaging, particularly during primary staging, treatment response assessment, and evaluation of suspected local recurrence.

Scarring/wound healing

In normal tissues, fibroblasts are quiescent but become activated after injury, inflammation, or fibrotic remodelling, leading to transient FAP expression during wound healing after trauma, surgery, radiotherapy, or inflammatory injury.[59] Post-interventional FAPI uptake typically appears as linear uptake along surgical scars, focal activity at anastomotic or operative sites, or persistent uptake around foreign materials such as mesh or implants.^[60] A retrospective study reported uptake in ~15% of intervention sites (mean SUVmax 3.2; range 1.5–5.1), usually resolving within ~8 months unless foreign materials were present.^[61]

Muscle uptake

Muscular FAPI uptake may reflect fibroblast activation related to skeletal muscle regeneration and extracellular matrix remodelling. Chronic mechanical loading has been proposed as one possible explanation, although this mechanism remains insufficiently validated in clinical imaging studies.^[61] Suh et al. reported a moderate positive correlation between skeletal muscle FAPI SUVmean and age and a negative correlation with muscle density, consistent with fatty infiltration and reduced muscle quality.^[62] Although benign tissues usually show lower uptake than malignancies (mean SUVmax ~4.2 vs ~10.6), substantial overlap exists, and no reliable thresholds are established; therefore, the clinical significance of muscular FAPI uptake remains uncertain.^[63] Unusual focal uptake patterns may also occur in structures not typically emphasised in standard interpretation frameworks. Previously underrecognized examples include uptake within the anorectal sphincter complex, which may represent a benign physiologic or functional pattern rather than metastatic or infiltrative pelvic disease. Awareness of such atypical uptake sites is important to reduce overcalling of incidental findings.^[64]

Physiologic uterine uptake

Physiologic uterine FAPI uptake is hormonally driven and reflects stromal and myometrial remodelling during menstrual cycles.^[65,66] Estrogen and progesterone stimulate FAP expression, producing diffuse uptake mainly in the uterine body, most often in reproductive-age women (>70%).^[5] Reported SUVmax values vary widely (≈1.3–24) and are lower in postmenopausal women. This background activity can reduce lesion contrast and complicate the evaluation of uterine pathology, requiring correlation with hormonal status and anatomical imaging.^[5]

Physiologic breast uptake

Physiologic breast FAPI uptake is hormonally driven and reflects stromal and fibroglandular remodelling associated with estrogen stimulation. It typically appears as diffuse, symmetric uptake in the breast parenchyma, often with symmetric nipple activity. Uptake varies with the menstrual cycle, showing higher SUVs during high-estrogen phases (median ~3.9) compared with moderate (median ~1.6) or low-estrogen states such as menopause (median ~1.0).^[5] Exogenous hormonal stimulation may further increase background activity ^[67–69], potentially obscuring small lesions and reducing detection sensitivity.^[67-69]

Reactive lymph nodes

FAPI uptake in lymph nodes is related to activation of fibroblastic reticular cells and stromal elements, which may occur in both metastatic infiltration and inflammatory or granulomatous conditions.^[70,71] Although several studies suggest FAPI PET may show higher specificity than FDG for nodal metastases in cancers such as lung and head-and-neck tumours,^[72-74] false-positive uptake can occur; for example, reactive lymphoid hyperplasia with SUVmax up to 17 has been reported.^[44] In contrast, vaccine-related axillary lymph nodes show minimal FAPI uptake compared with intense FDG activity.^[75] Therefore, nodal FAPI findings should be interpreted cautiously and correlated with imaging, clinical context, or follow-up.

Post-interventional uptake

Post-interventional uptake is another important source of non-malignant FAPI activity. In the pancreaticobiliary setting, diffuse tracer uptake surrounding a recently placed pancreatic stent has been reported, reflecting procedure-related inflammatory remodelling rather than recurrent tumour. Recognition of this pattern is particularly important in patients imaged shortly after stent manipulation or replacement.^[76] A schematic overview of nonmalignant FAPI uptake across inflammatory, fibrotic, physiologic, post-interventional, and benign stromal-rich conditions is presented in Fig 3.

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Fig 3: Schematic overview of nonmalignant Fibroblast activation protein inhibitor uptake across inflammatory, fibrotic, physiologic, post-interventional, and benign stromal-rich conditions.

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Diagnostic pitfalls and quantitative challenges

As FAPI PET/CT becomes increasingly integrated into oncologic imaging, recognition of diagnostic pitfalls and non-malignant uptake patterns has become essential for accurate interpretation. Real-world clinical data demonstrate that incidental benign uptake is not uncommon but rather a frequent finding in the routine practice of FAPI PET/CT. In a tertiary-centre retrospective analysis, 220 diagnostic pitfalls were identified across 88.3% of examinations, with musculoskeletal degenerative changes, inflammatory conditions, and benign tumours accounting for a substantial proportion of unexpected findings. These data emphasise that non-malignant FAPI uptake is common in daily practice and should be systematically considered during image interpretation.^[7]

Accordingly, FAPI PET/CT interpretation should integrate the uptake pattern, anatomic correlate, clinical context, and timing. Diffuse or symmetric uptake favours benign processes, whereas focal uptake without a CT correlate warrants caution. Correlation with imaging, clinical history, or follow-up may be required, as SUV alone is insufficient for reliable characterisation. Practical features that may help distinguish benign from malignant FAPI uptake on PET/CT are summarised in Table 2.

SUV overlap between benign and malignant lesions

SUVmax reflects uptake in a single voxel and may not represent overall lesion burden or heterogeneity. It is affected by technical factors (scanner calibration, reconstruction, ROI definition) and biological variables such as motion and uptake timing, which can alter SUVmax by up to 30%.^[77] Consequently, SUVmax alone may be unreliable, particularly in non-malignant conditions where FAPI uptake can be subtle or heterogeneous; complementary metrics such as SUVmean, volumetric parameters, and target-to-background ratios may improve assessment.^[77]

Influence of tracer type (⁶⁸Ga vs ¹⁸F)

Differences between FAP-targeting tracers, including 68Ga-labelled agents (FAPI-02, -04, -46) and 18F-labelled variants (e.g., FAPI-74), may limit direct comparison across studies because variations in pharmacokinetics, tumour retention, and radionuclide properties influence tracer distribution and interpretation.^[78] Clearance patterns also differ: 68Ga-FAPI tracers are primarily renally excreted, whereas 18F-FAPI-74 shows both biliary and urinary excretion, with activity in the bile ducts and gallbladder that may complicate the interpretation of upper abdominal lesions.^[79,80] Both tracers provide high tumour contrast, typically with optimal imaging around 1 hour post-injection and SUVmax values often >10 in malignant lesions, while 18F-FAPI-74 PET/CT has a low radiation dose (~1.4 ± 0.2 mSv per 100 MBq), supporting its clinical feasibility.^[80]

Timing post-injection

Optimal imaging timing remains a limitation of FAPI PET/CT, as dynamic studies have shown that lesion detectability may be reduced with very early acquisition (≈10 min post-injection), while similar detection performance was observed at 30–60 min post-injection, suggesting that inappropriate timing could potentially lead to missed lesions [Fig 4].^[80,81]

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Fig 4: Time-dependent 18F-FAPI-74 PET imaging. (A) Maximum-intensity projections at 10 min, 1 h, and 3 h post-injection demonstrate the dynamic tracer kinetics and evolving tumour-to-background contrast. The red dashed lines indicate the axial levels corresponding to the cross-sectional images shown in panels B–E. (B) FAPI PET/CT allows clear discrimination between tumour and myocardium (red arrows). (C) Lesions confirmed by CT are indicated by red arrows. (D, E) Additional bone metastases detected exclusively on FAPI PET are indicated by red arrows, demonstrating how lesion detectability varies over time. Adapted from^[80] under CC BY 4.0. FAPI: Fibroblast activation protein inhibitor; PET/CT: Positron emission tomography/computed tomography

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A prospective study assessing optimal imaging timing for FAPI PET/CT used 60-min dynamic total-body scans reconstructed at 10-min intervals. Image quality, evaluated by SUV, liver signal-to-noise ratio, and lesion-to-background ratios, improved over time as background activity decreased, with some lesions becoming detectable only after 30–40 min post-injection. Analysis of overlapping 5-min intervals showed that 34–39 min imaging provided lesion detection and contrast comparable to the standard 50–60 min acquisition [Fig 5].^[82]

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Fig 5: Suggested post-injection imaging timeline for FAPI PET/CT, adapted from published timing data.^[82] FAPI: Fibroblast activation protein inhibitor; PET/CT: Positron emission tomography/computed tomography

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Implications for radioligand therapy

Future directions

Future research on non-malignant FAPI uptake should aim to better define its biological specificity and clinical utility across inflammatory and fibrotic diseases. Although current evidence shows that FAPI uptake reflects fibroblast activation during tissue remodelling, distinguishing malignant stromal activation from benign fibro-inflammatory processes remains a key diagnostic challenge. Large prospective cohorts are needed to systematically characterise uptake patterns, SUV ranges, and temporal behaviour of FAPI in non-oncologic conditions such as autoimmune diseases, chronic infections, and organ fibrosis. Establishing reference patterns may improve interpretation criteria and reduce false-positive findings during oncologic imaging. The development of standardised interpretation criteria, analogous to PROMISE criteria for PSMA PET, may help reduce variability in FAPI PET interpretation.

Beyond diagnostic applications, FAPI imaging may also evolve into a tool for monitoring antifibrotic or immunomodulatory therapies. The ability to noninvasively visualise activated fibroblasts could enable earlier assessment of treatment response before structural changes become apparent on conventional imaging. In addition, the high expression of fibroblast activation protein in fibrotic and fibro-inflammatory tissues raises the possibility of FAPI-based theranostic strategies. Radiolabelled FAP inhibitors such as 177Lu-FAPI could potentially target activated fibroblasts to modulate pathological fibrosis.

Another important research priority is determining the optimal timing of imaging for non-malignant conditions. Current protocols typically rely on early imaging after tracer injection, which were largely optimised for oncologic applications. However, inflammatory and fibrotic lesions may demonstrate different tracer kinetics. Future studies should evaluate dual-time-point or delayed imaging to determine whether these approaches improve differentiation between inflammation, fibrosis, and malignancy.