European Nuclear Medicine Guide
[68Ga]Ga-PentixaFor
[68Ga]Ga-PentixaFor is a radiolabelled cyclic pentapeptide antagonist that selectively binds to the C-X-C chemokine receptor 4 (CXCR4), a G-protein-coupled receptor overexpressed in various malignancies and inflammatory conditions [338]. It is highly expressed in various immune cell subsets, including macrophages and T cells [339]. CXCR4 also plays a pivotal role in cell migration, tumour progression, and metastasis [340].
[68Ga]Ga-PentixaFor PET imaging has demonstrated utility in several lymphoproliferative disorders (LPDs) [341], including multiple myeloma (MM) [342-345], mantle cell lymphoma (MCL) [346], marginal zone lymphoma (MZL) [347-349] Waldenström's macroglobulinaemia (WM) [350, 351], chronic lymphocytic leukaemia (CLL) [352, 353], acute myeloid leukaemia (AML) [354,355], and non-Hodgkin lymphoma (NHL) [356].
In solid tumours, [68Ga]Ga-PentixaFor has shown initial promise in imaging adrenocortical carcinoma (ACC) [357–360], gliomas [361,362], head and neck squamous cell carcinoma (HNSCC) [363–365], breast cancer [366] and small cell as well as non-small cell lung cancer (SCLC and NSCLC) [367,368].
For primary aldosteronism (PA), particularly in subtyping aldosterone-producing adenomas (APAs), [68Ga]Ga-PentixaFor PET/CT offers a non-invasive alternative to adrenal vein sampling (AVS), demonstrating high sensitivity and specificity [369–371].
Due to its ability to visualize leukocyte trafficking, [68Ga]Ga-PentixaFor PET imaging has also found clinical applicability in assessing inflammatory conditions such as atherosclerosis [372–375], myocardial infarction [376, 377], idiopathic pulmonary fibrosis [378], and various kinds of infections [379, 380].
Pregnancy; breastfeeding should be discontinued 4–12 hours prior to imaging [381].
The administered activity of [68Ga]Ga-PentixaFor varies depending on the clinical indication and patient characteristics. Typical activities range from 1.85 to 4 MBq/kg (100–200 MBq/patient) [381].
Dosimetric assessments indicate that [68Ga]Ga-PentixaFor has a favourable safety profile. For a standard administration of 150 MBq, the effective dose is estimated at 2.3 mSv [381]. The urinary bladder wall receives the highest absorbed dose (12.2 mGy), followed by the spleen (8.1 mGy), kidneys (5.3 mGy), and heart wall (4.0 mGy). Doses are lower in other organs such as the liver (2.7 mGy), red bone marrow (2.1 mGy) testes (1.7 mGy) and ovaries (1.9 mGy).
[68Ga]Ga-PentixaFor PET/CT has shown excellent clinical performance in imaging lymphoproliferative disorders, where CXCR4 is commonly overexpressed. In multiple myeloma, it enables detection of both intra- and extramedullary lesions and outperforms [18F]FDG PET/CT in detecting bone marrow involvement and extramedullary disease, especially in cases with low FDG uptake [342]. In mantle cell lymphoma, [68Ga]Ga-PentixaFor PET/MRI has demonstrated superior diagnostic sensitivity (100%) compared to [18F]FDG PET/MRI (75.2%), particularly for nodal and extranodal involvement [346]. Similarly, in marginal zone lymphoma, the tracer provided improved staging accuracy, frequently leading to changes in clinical management [347]. Additionally, preliminary clinical evidence also supports its application in various other B-cell and T-cell neoplasms, including central nervous system lymphoma [382-384], CLL [352, 353], acute myeloid leukaemia (AML) [354], and other non-Hodgkin lymphomas [356]. Overall, [68Ga]Ga-PentixaFor offers high lesion conspicuity and favorable lesion-to-background contrast, supporting its role as a promising alternative or adjunct to [18F]FDG in selected haematological malignancies.
[68Ga]Ga-PentixaFor PET imaging has been explored in a variety of solid tumours where CXCR4 expression is implicated in tumour progression and metastasis. Uptake has been observed in malignancies such as adrenocortical carcinoma, gliomas, head and neck squamous cell carcinoma, breast cancer, and small cell lung cancer.
In patients with ACC, [68Ga]Ga-PentixaFor PET/CT effectively visualized both primary ACC tumours and metastatic sites, including local recurrences and peritoneal metastases [359, 360]. Chemokine receptor binding on the tumour cell surface has been demonstrated as an independent predictor for overall survival [359].
Studies have shown variability in CXCR4 expression among metastatic nodules, with PET SUVs correlating well with immunohistochemistry (IHC) and mRNA levels of CXCR4 [357]. While [68Ga]Ga-PentixaFor provides good tumour-to-background contrast, its TBR is generally lower than that of [18F]FDG in ACC imaging [357]. In some cases, however, [68Ga]Ga-PentixaFor identified additional metastatic lesions not detected by [18F]FDG, but this occurred in a minority of patients (~9%).
It is of note that in a retrospective analysis including 30 subjects with advanced, metastasized ACC, seventy per cent might have been suitable for CXCR4-directed treatment [385].
In gliomas, [68Ga]Ga-PentixaFor PET/CT has demonstrated a 93.1% detection rate for high-grade gliomas, outperforming conventional MRI in distinguishing tumour tissue from treatment-induced changes. Furthermore, [68Ga]Ga-PentixaFor PET/CT showed excellent accuracy in tumour grading, with Grade IV gliomas showing significantly higher SUVmax (median 2.85 vs. 1.27 in grade III) and tumour-to-background ratios (TBR) [361, 362]. While a significant inter- and intra-tumour variation in GBM has been described, high CXCR4 expression has been found in a subset of tumour cores, potentially rendering selected patients candidates for targeted radioligand therapy in the future [386].
Interestingly, the cranial bone marrow has recently been discovered to harbour tumour-reactive CD8+ effector types expressing CXCR4 on the cell surface, with calvarial CXCR4 uptake showing a positive correlation with improved patient outcome [387].
In head and neck cancer, [68Ga]Ga-PentixaFor PET/CT achieves a detection rate of 96%, comparable to [18F]FDG PET/CT for primary tumours in nasopharyngeal carcinoma (NPC), despite lower absolute tracer uptake [364]. The correlation between [68Ga]Ga-PentixaFor PET signal and CXCR4 IHC staining underscores the value of [68Ga]Ga-PentixaFor PET for patient selection for CXCR4-targeted therapies [363, 365].
In breast cancer, [68Ga]Ga-PentixaFor PET/CT was able to detect primary breast cancer with 96% sensitivity and 100% specificity, outperforming conventional imaging in certain scenarios. TNBC exhibits significantly higher [68Ga]Ga-PentixaFor uptake (SUVmax = 7.26 ± 2.84) compared to luminal subtypes, correlating with tumour aggression and proliferative index (Ki-67). Furthermore, [68Ga]Ga-PentixaFor PET/CT has shown efficacy in detecting brain, skull, liver, bone, and lymph node metastases with moderate uptake (mean SUVmax: 4.9–5.34), although [18F]FDG remains superior for detection of bone marrow metastases [366].
In lung cancer, [68Ga]Ga-PentixaFor PET/CT has shown some utility in tumour subtype differentiation. For example, [68Ga]Ga-PentixaFor PET/CT achieves an 85.7% sensitivity and 78.1% specificity for distinguishing small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) using an SUVmax cut-off of 7.2 [368]. Furthermore, SCLC exhibits higher CXCR4 expression (mean SUVmax = 10.3 ± 5.0) compared to NSCLC (6.2 ± 2.1 for squamous cell; 8.0 ± 1.9 for adenocarcinoma). SUVmax thresholding at 6.7 additionally allowed differentiation of lung adenocarcinoma from squamous cell carcinoma with 87.5% sensitivity and 71.4% specificity [368].
[68Ga]Ga-PentixaFor PET/CT achieved a sensitivity of 92.4%, specificity of 94.4%, and overall accuracy of 93.3% for identifying APA. For adrenal nodules >1 cm, a SUVmax threshold of ≥7.3 yielded 100% specificity, while it also performed well for nodules <1 cm [371]. In patients with adrenal micronodules (<1 cm), [68Ga]Ga-PentixaFor PET/CT demonstrated significantly higher sensitivity (90.2%), specificity (72.7%), and accuracy (86.5%) compared to adrenal CT (sensitivity: 73.1%, specificity: 53.8%, accuracy: 68.3%) [373]. Furthermore, the concordance rate between [68Ga]Ga-PentixaFor PET/CT and adrenal venous sampling (AVS), the current gold standard, was 77%. PET/CT identified additional cases of unilateral primary aldosteronism (UPA) that AVS missed, enabling better surgical planning [370], with a higher concordance with surgical outcomes (82.4% vs. 68.9%) in identifying surgically curable lesions [369]. A current prospective phase II trial is investigating the accuracy of [68Ga]Ga-PentixaFor PET/CT in diagnosing primary aldosteronism in comparison to AVS (CASTUS; NL9625).
The high CXCR4 expression in inflammatory cells, particularly macrophages [339], also makes [68Ga]Ga-PentixaFor PET/CT highly effective in imaging atherosclerotic plaques [372–375], myocardial infarction, infections [379, 380], and idiopathic pulmonary fibrosis [379].
In atherosclerosis, [68Ga]Ga-PentixaFor PET/CT detected more lesions compared to [18F]FDG PET (88% vs. 48%, p < 0.001), providing higher uptake and target-to-background ratios (TBR), with TBR values of 1.90 ± 0.29 for Pentixafor versus 1.63 ± 0.29 for FDG (p < 0.001) [372, 373]. Studies demonstrate a negative correlation between tracer uptake and arterial calcification, suggesting that CXCR4-directed imaging identifies active inflammation rather than stable calcified plaques [372].
In myocardial infarction, [68Ga]Ga-PentixaFor PET/CT was able to visualize recruitment of CXCR4-positive inflammatory cells (e.g., macrophages, neutrophils, monocytes) to the damaged myocardium (0–13 days post-infarction), with good contrast between affected and unaffected areas (infarct-to-remote ratio of 2.2 ± 0.4 and infarct-to-left cavity ratio of 1.4 ± 0.1) [376, 377] Early CXCR4 imaging was found to be able to predict outcomes such as left ventricular remodelling and ejection fraction recovery [388, 389]. Increased tracer uptake was also observed in systemic organs like the bone marrow and spleen, reflecting systemic inflammation and immune cell mobilization [390].
Recently, [68Ga]Ga-PentixaFor PET/CT was also found to be a valuable tool for assessing the extent of idiopathic lung fibrosis [378]. Average tracer uptake (SUVmean) in fibrotic areas was 2.3 ± 0.5, with variability between patients (range: 1.6–3.0). [68Ga]Ga-PentixaFor PET/CT has also shown utility for imaging changes in lung CXCR4 expression in response to antifibrotic treatment, which led to a reduction in fibrotic areas by an average of 27 ± 9% [378].
Interpretation of [68Ga]Ga-PentixaFor PET images involves both visual and semi-quantitative assessments. In cancer, evaluation is generally based on maximum standardized uptake values (SUVmax), tumour-to-background ratios (TBR), and in some cases a 5-point Likert scale [363]. For primary aldosteronism, lesion-to-adrenal ratio (LAR), lesion-to-contralateral ratio (LCR) and lesion-to-liver ratio (LLR) are utilized alongside SUV metrics [369]. In atherosclerotic plaque assessment and IPF, specifically defined target-to-background ratios are used to differentiate active inflammation from normal tissue.
While [68Ga]Ga-PentixaFor PET/CT imaging offers valuable insights into CXCR4 expression across various pathologies, several pitfalls must be borne in mind to ensure accurate image interpretation:
High physiological uptake of [68Ga]Ga-PentixaFor is commonly observed in the spleen and bone marrow due to their rich populations of CXCR4-expressing haematopoietic and immune cells. This uptake can vary significantly based on the individual's immune status. For instance, in patients with systemic immune activation—such as those with infections, autoimmune conditions, or individuals undergoing immune reconstitution therapy—there may be increased tracer accumulation in these organs. This heightened physiological uptake can complicate the differentiation between normal and pathological findings, particularly when assessing for disease involvement in these regions.
Especially in solid tumours, pilot studies have reported a more heterogeneous in vivo CXCR4 expression profile than might have been expected from the in vitro CXCR4 expression profile described in the literature [391,392]. Even in haematological diseases such as MM or DLBCL, some lesions may have low or absent CXCR4 expression, leading to false-negative results [358, 393].
[68Ga]Ga-PentixaFor PET/CT may also be influenced by concomitant tumour treatment, including external beam radiation or chemotherapy. In a preliminary case series featuring three subjects with MM, DLBCL and ALL scheduled for CXCR4-directed radiopharmaceutical therapy, altered CXCR4 surface expression was observed as a response to non-lethal bridging chemotherapy [394]. While receptor up-regulation on the cell surface of MM and DLBCL cell lines could also be induced by therapeutic agents such as dexamethasone or doxorubicine [395, 396], further research is warranted to better understand time- and dose-dependent effects as well as the underlying mechanisms involved.
CXCR4 is not exclusively expressed in malignant cells; it is also up-regulated in various inflammatory and infectious processes. Consequently, [68Ga]Ga-PentixaFor PET/CT may show increased uptake in areas of inflammation, such as sites of infection, autoimmune activity, or tissue repair. This non-specific uptake necessitates careful correlation with clinical findings and other diagnostic modalities.
[68Ga]Ga-PentixaFor PET/CT requires no specific patient preparation.
Whole-body acquisition vertex to mid-thigh (extend to toes or whole-body if clinically indicated), after 50–70 minutes post-injection (most studies use 60 ±15 min) [381].