PET Tracer Research Articles

Longitudinal multimodal monitoring of transplanted islet β-cells

PurposeMonitoring β-cell mass and function would provide a better understanding of diabetes, setting the stage for truly individualized therapies. We applied a combined PET/MRI protocol to monitor engrafted islets mass and function without pre-labeling of isolated cells. A PET tracer binding to GLP-1R quantifies β-cell mass, while Mn-CA characterizes β-cell function. Both parameters were assessed in transplanted and native β-cells in vivo and validated with autoradiography and mass spectrometry imaging. MethodsIslets were collected and transplanted into the calves of C3H-mice. Accumulation of [64Cu]Ex4 and Mn-CA was examined with a PET/MRI at 1 h post-injection between 1 and 4 weeks after the transplantation. A separate blocking study with diazoxide targeted the functionality of the transplanted islets. As validation, ex vivo autoradiography and LA-ICP-MS imaging were performed after the last imaging session. ResultsPET/MRI monitored the engraftment of transplanted islets and visualized an increasing uptake of the PET tracer and Mn-CA. The Mn-CA accumulated at a higher islet-to-background ratio in the calf of mice than in the pancreas due to the high retention of Mn-CA in the exocrine pancreas. In vivo imaging data correlated well with autoradiography and LA-ICP-MS imaging, validating the in vivo approaches. ConclusionFor the quantification of β-cell function, Mn-based contrast mechanisms between native and transplanted islets differ and require further studies for optimal biological readout. However, non-invasive PET/MRI nonetheless provides the tools to investigate the relationship between β-cell mass and function in pancreatic islets.

P1.09C.03 IMMUNOResist: Defining the Immunophenotype of Immunotherapy Resistance with PD-L1 and CD8 Novel Tracer PET

P1.09C.03 IMMUNOResist: Defining the Immunophenotype of Immunotherapy Resistance with PD-L1 and CD8 Novel Tracer PET

Design, Synthesis, and Preclinical Evaluation of a High-Affinity 18F-Labeled Radioligand for Myocardial Growth Hormone Secretagogue Receptor Before and After Myocardial Infarction.

The peptide hormone ghrelin is produced in cardiomyocytes and acts through the myocardial growth hormone secretagogue receptor (GHSR) to promote cardiomyocyte survival. Administration of ghrelin may have therapeutic effects on post-myocardial infarction (MI) outcomes. Therefore, there is a need to develop molecular imaging probes that can track the dynamics of GHSR in health and disease to better predict the effectiveness of ghrelin-based therapeutics. We designed a high-affinity GHSR ligand labeled with 18F for imaging by PET and characterized its invivo properties in a canine model of MI. Methods: We rationally designed and radiolabeled with 18F a quinazolinone derivative ([18F]LCE470) with subnanomolar binding affinity to GHSR. We determined the sensitivity and invivo and ex vivo specificity of [18F]LCE470 in a canine model of surgically induced MI using PET/MRI, which allowed for anatomic localization of tracer uptake and simultaneous determination of global cardiac function. Uptake of [18F]LCE470 was determined by time-activity curve and SUV analysis in 3 regions of the left ventricle-area of infarct, territory served by the left circumflex coronary artery, and remote myocardium-over a period of 1.5 y. Changes in cardiac perfusion were tracked by [13N]NH3 PET. Results: The receptor binding affinity of LCE470 was measured at 0.33 nM, the highest known receptor binding affinity for a radiolabeled GHSR ligand. In vivo blocking studies in healthy hounds and ex vivo blocking studies in myocardial tissue showed the specificity of [18F]LCE470, and sensitivity was demonstrated by a positive correlation between tracer uptake and GHSR abundance. Post-MI changes in [18F]LCE470 uptake occurred independently of perfusion tracer distributions and changes in global cardiac function. We found that the regional distribution of [18F]LCE470 within the left ventricle diverged significantly within 1 d after MI and remained that way throughout the 1.5-y duration of the study. Conclusion: [18F]LCE470 is a high-affinity PET tracer that can detect changes in the regional distribution of myocardial GHSR after MI. In vivo PET molecular imaging of the global dynamics of GHSR may lead to improved GHSR-based therapeutics in the treatment of post-MI remodeling.

18F]Trifluoroiodomethane - Enabling Photoredox-mediated Radical [18F]Trifluoromethylation for Positron Emission Tomography.

The development of new tracers for positron emission tomography (PET) is highly dependent on the available synthetic tools for their radiosynthesis. Herein, we present the radiosynthesis and application of [18F]trifluoroiodomethane - the first reagent for broad scope radical [18F]trifluoromethylation chemistry in high molar activity. CF2 18FI can be prepared from [18F]fluoroform with 67±5 % AY and >99 % RCP. Its synthetic utility is demonstrated by the radiosynthesis of previously unprecedented 18F-labeled α-trifluoromethyl ketones and 18F-labeled trifluoromethyl sulfides, important motifs that are present in a range of bioactive compounds. Both protocols are Ru- and photo-mediated and proceed under mild reaction conditions. They show good functional group tolerance evidenced by the respective reaction scopes and make use of easily obtainable starting materials. The products can be isolated in 8.3-11.1 GBq/μmol (starting from ca. 5GBq [18F]fluoride). The applicability to PET tracer synthesis is shown by the radiolabeling of bioactive compounds, such as derivatives of probenecid and febuxostat. In a broader context, this work opens the door to the utilization of radical [18F]trifluoromethylation chemistry for the radiolabeling of PET tracers in high molar activity.

“[18F]Trifluoroiodomethane – Enabling Photoredox‐mediated Radical [18F]Trifluoromethylation for Positron Emission Tomography

The development of new tracers for positron emission tomography (PET) is highly dependent on the available synthetic tools for their radiosynthesis. Herein, we present the radiosynthesis and application of [18F]trifluoroiodomethane – the first reagent for broad scope radical [18F]trifluoromethylation chemistry in high molar activity. CF218FI can be prepared from [18F]fluoroform with 67±5% AY and >99% RCP. Its synthetic utility is demonstrated by the radiosynthesis of previously unprecedented 18F‐labeled a‐trifluoromethyl ketones and trifluoromethyl sulfides, important motifs that are present in a range of bioactive compounds. Both protocols are Ru‐ and photo‐mediated and proceed under mild reaction conditions. They show good functional group tolerance evidenced by the respective reaction scopes and make use of easily obtainable starting materials. The products can be isolated in 8.3‐11.1 GBq/µmol (starting from ca. 5 GBq [18F]fluoride). The applicability to PET tracer synthesis is shown by the radiolabeling of bioactive compounds, such as derivatives of probenecid and febuxostat. In a broader context, this work opens the door to the utilization of radical [18F]trifluoromethylation chemistry for the radiolabeling of PET tracers in high molar activity.

Crossover evaluation of time-of-flight-based attenuation correction in brain 18F-FDG and 18F-flutemetamol PET.

Brain-dedicated positron emission tomography (PET) systems offer high spatial resolution and sensitivity for accurate clinical assessments. Attenuation correction (AC) is important in PET imaging, particularly in brain studies. This study assessed the reproducibility of attenuation maps (µ-maps) generated by a specialized time-of-flight (TOF) brain-dedicated PET system for imaging using different PET tracers. Twelve subjects underwent both 18F-fluorodeoxyglucose (FDG)-PET and 18F-flutemetamol (FMM) amyloid-PET scans. Images were reconstructed with µ-maps obtained by a maximum likelihood-based AC method. Voxel-based and region-based analyses were used to compare µ-maps obtained with FDG-PET versus FMM-PET; FDG-PET images reconstructed using an FDG-PET µ-map (FDG × FDG) versus those reconstructed with an FMM-PET µ-map (FDG × FMM); and FMM-PET images reconstructed using an FDG-PET µ-map (FMM × FDG) versus those reconstructed with an FMM-PET µ-map (FMM × FMM). Small but significant differences in µ-maps were observed between tracers, primarily in bone regions. In the comparison between the µ-maps obtained with FDG-PET and FMM-PET, the µ-maps obtained with FDG-PET had higher µ-values than those obtained with FMM-PET in the parietal regions of the head and skull, in a portion of the cerebellar dentate nucleus and on the surface of the frontal lobe. The comparison between FDG and FDG × FMM values in different regions yielded findings similar to those of the µ-maps comparison. FDG × FMM values were significantly higher than FDG values in the bilateral temporal bones and a small part of the temporal lobe. Similarly, FMM values were significantly higher than FMM × FDG values in the bilateral temporal bones. FMM × FDG values were significantly higher than FMM values in a small area of the right cerebellar hemisphere. However, the relative errors in these µ-maps were within ± 4%, suggesting that they are clinically insignificant. In PET images reconstructed with the original and swapped µ-maps, the relative errors were within ± 7% and the quality was nearly equivalent. These findings suggest the clinical reliability of the AC method without an external radiation source in TOF brain-dedicated PET systems.

Metachronous Second Primary in the Form of Nasopharyngeal Carcinoma Following Treatment of Small Cell Neuroendocrine Carcinoma of the Head and Neck: Dual Tracer PET/CT Findings Highlighting SSTR2 Expression and Its Theranostic Implications

AbstractPatients of head and neck squamous cell carcinoma (HNSCC) experience increased risk of developing second primary cancer (SPC) necessitating active surveillance during their disease course. SPCs are associated with poor prognosis and are the leading cause of long-term morbidity and mortality impacting survival of patients with HNSCC. Small cell neuroendocrine carcinoma (SmNEC) is a rare but aggressive neoplasm with poor prognosis and high risk of local recurrence and distant metastasis. We report an exceedingly rare case of nasopharyngeal carcinoma (NPC) presenting as a recurrence in the form of metachronous second primary to primary SmNEC 9 years after chemotherapy. The dual tracer positron emission tomography and computed tomography (PET/CT) imaging approach ([68Ga]Ga-DOTATATE-PET/CT with 18F-FDG-PET/CT) was explored in such metachronous NPCs, and the findings are illustrated with its potential for theranostic applications. NPC is a rare malignancy with significant geographical variations in incidence rates. Somatostatin receptor 2 (SSTR2) expression in NPC is well documented and can serve as a potential theragnostic marker in advanced NPC where the successful outcome is minimal with currently available treatment modalities.

The Development and Evaluation of a Novel Highly Selective PET Radiotracer for Targeting BET BD1.

Background/Objectives: Small molecules that interfere with the interaction between acetylated protein tails and the tandem bromodomains of BET (bromodomain and extra-terminal) family proteins are pivotal in modulating immune/inflammatory and neoplastic diseases. This study aimed to develop a novel PET imaging tracer, [11C]GSK023, that targets the N-terminal bromodomain (BD1) of BET family proteins with high selectivity and potency, thereby enriching the chemical probe toolbox for epigenetic imaging. Methods: [11C]GSK023, a radio-chemical probe, was designed and synthesized to specifically target the BET BD1. In vivo PET imaging evaluations were conducted on rodents, focusing on the tracer's distribution and binding specificity in various tissues. Blocking studies were performed to confirm the probe's selectivity and specificity. Results: The evaluations revealed that [11C]GSK023 demonstrated good uptake in peripheral organs with limited brain penetration. Further blocking studies confirmed the probe's high binding specificity and selectivity for the BET BD1 protein, underscoring its potential utility in epigenetic imaging. Conclusions: The findings suggest that [11C]GSK023 is a promising PET probe for imaging the BET BD1 protein, offering the potential to deepen our understanding of the roles of BET bro-modomains in disease and their application in clinical settings to monitor disease progression and therapeutic responses.

Reproducibility of [18F]MK-6240 kinetics in brain studies with shortened dynamic PET protocol in healthy/cognitively normal subjects

Background[18F]MK-6240 is a neurofibrillary tangles PET radiotracer that has been broadly used in aging and Alzheimer’s disease (AD) studies. Majority of [18F]MK-6240 PET studies use dynamic acquisitions longer than 60 min to assess the tracer kinetic parameters. As of today, no consensus has been established on the optimum dynamic PET scan time. In this study, we assess the reproducibility of [18F]MK-6240 quantitative metrics using shortest dynamic PET protocols in cognitively normal subjects. PET metrics were measured through two-tissue compartment model (2TCM) and Logan model to estimate VT and DVR, as well as SUVR from 90 to 120 min (SUVR90 − 120 min) post-tracer injection for brain regions. 2TCM was carried out using the 120 min dynamic coffee break dataset (first scan from 0 to 60 min p.i., second scan from 90 to 120 min p.i.) and then repeated after stepwise shortening it by 5 min. The dynamic scan length that reproduced the 120 min dynamic scans-based VT to within 10% error was defined as the shortest acquisition time (SAT). The SAT SUVR90 − 120 min was deduced from the SAT dataset by extrapolation of each image pixel time-activity curve to 120 min. The reproducibility of the 120 min dynamic scans-based VT2TCM, DVR2TCM, DVRLogan, and SUVR using the SAT was assessed using Passing-Bablock analysis. The limits of reproducibility of each PET metrics were determined using Bland-Altman analysis.ResultsA dynamic SAT of 40 min yielded < 10% error in [18F]MK-6240 VT2TCM’s for all brain regions, compared to those measured using the 120 min datasets. SAT-based analysis did not show statistically significant systemic or proportional biases in VT2TCM, DVR2TCM, DVRLogan, or SUVR compared to those deduced from the full dynamic dataset of 120 min. A mean difference between the 120 min- and SAT-based analysis of less than 4%, 10%, 15%, and 20% existed in the VT2TCM, DVR2TCM, DVRLogan, and SUVR respectively.ConclusionKinetic modeling of [18F]MK-6240 PET can be accurately performed using dynamic scan times as short as 40 min. This can facilitate studies with [18F]MK-6240 PET and improve patients accrual. Further work would be necessary to confirm the reproducibility of these results for patients in dementia spectra.

Effectiveness of electro-acupuncture for cognitive improvement on Alzheimer's disease quantified via PET imaging of sphingosine-1-phosphate receptor 1.

Electro-acupuncture (EA) has demonstrated potential in improving mild-to-moderate dementiain clinics, but the underlying scientific target remains unclear. EA was administered to APP/PS1 Alzheimer's disease (AD) mice, with untreated AD, and wild type (WT) mice serving as controls. The efficacy of EA was assessed by the Morris water mazecognitive functional tests. Brain magnetic resonance imaging-positron emission tomography (PET) scans using [18F]TZ4877 targeting sphingosine-1-phosphate receptor 1 (S1PR1) and [18F]AV45 targeting amyloid beta fibrils were conducted. The correlation between regionalbrain PET quantificationsand cognitive functions was analyzed. EA significantlyimproved cognitive and memoryfunctions of AD (p = 0.04) and reduced the uptake of [18F]TZ4877 in the cortex (p = 0.02) and hippocampus (p = 0.03). Immunofluorescence confirmed colocalizations of S1PR1 with glial fibrillary acidic protein and ionized calcium-binding adaptor molecule-1. Furthermore, immunohistochemistry showed a significant reduction of interleukin 1β and tumor necrosis factor α after EA treatment. EA may reverse AD by suppressing neuroinflammation, and the PET imaging of S1PR1 seemed potent in evaluating the treatment for AD patients HIGHLIGHTS: Electro-acupuncture (EA) was administered to APP/PS1 Alzheimer's disease (AD) mice, with untreated AD, and wild type (WT) mice serving as controls. The efficacy of EA was assessed by the Morris water maze cognitive functional tests and positron emission tomography (PET) imaging quantifications. PET tracer [18F]AV45 was used to detect amyloid beta deposition. An increased uptake of [18F]AV45 was found in AD compared to WT mice, with significance observed only in the cortex and not in the hippocampus. EA treatment exhibited a trend toward reduced [18F]AV45 uptake in AD mouse brains post-treatment. However, statistical difference was not attained in most brain regions. EA "Baihui (DU20) and Sishencong (EX-HN1)" significantly improved cognitive and memory functions of AD (p = 0.04). Brain magnetic resonance imaging p(MRI)-positron emission tomography (PET) quantifications revealed that significantly reduced the uptake of [18F]TZ4877 in the cortex (p = 0.02) and hippocampus (p = 0.03) after EA treatment. The correlation between PET quantifications and cognitive functions was analyzed and the most notable correlations were found between escape latency (reaction cognitive and memory behavior) and volume distribution (VT) quantifications of [18F]TZ4877. VT quantifications of [18F]TZ4877 in key brain regions for cognitive and memory ability, such as the cortex and hippocampus, positively correlated with platform latency (cortex p < 0.01, r = 0.7102; hippocampus p < 0.01, r = 0.6891). Immunofluorescence confirmed colocalizations of S1PR1 with glial fibrillary acidic protein and ionized calcium-binding adaptor molecule-1 in the AD brain. And the EA treatment significantly reduced the signals in the cortex and hippocampus. Immunohistochemistry showed a significant reduction of interleukin 1β and tumor necrosis factor α after EA treatment. EA reversed AD by suppressing neuroinflammation in the cortex and hippocampus. The S1PR1 targeting PET tracer [18F]TZ4877 showed promise in evaluating the pathological progression of AD in clinical settings.

Plasma biomarkers in chronic single moderate-severe traumatic brain injury.

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate-severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-β (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10-33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = -2.17, SE = 1.06, P = 0.043, 95% CI [-4.28, -0.07]; long delay: bP-tau = -2.56, SE = 1.08, P = 0.020, 95% CI [-4.71, -0.41]}, tau {immediate memory: bTau = -6.22, SE = 2.47, P = 0.014, 95% CI [-11.14, -1.30]} and UCH-L1 {immediate memory: bUCH-L1 = -2.14, SE = 1.07, P = 0.048, 95% CI [-4.26, -0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate-severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI.

Clinical Value of Dual Tracer PET Imaging With 68Ga-PSMA and 18F-FDG in Patients With Metastatic Prostate Cancer

In this study, we retrospectively analyzed the imaging characteristics of dual-tracer 68Ga-prostate specific membrane antigen (PSMA) and 18F-flurodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in metastatic prostate cancer (mPCa) patients. We analyzed the uptake modes of the dual tracers, explored clinical pathological parameters affecting the 18F-FDG uptake in the lesions, and evaluated their prognostic implications for prostate specific antigen progression-free survival (PSA-PFS). A total of 41 mPCa patients who underwent dual-tracer PET/CT (68Ga-PSMA and 18F-FDG) scans between September 2021 and January 2024 were retrospectively enrolled. One patient had negative uptake of both PSMA and FDG. According to the uptake patterns of the 2 tracers, the other patients, 40 in total, were categorized in 2 groups, including group A consisting of 33 cases who showed PSMA and FDG dual and those who showed FDG only avidity, and group B consisting of 7 cases who showed PSMA avidity only. Comparative analyses of clinical pathological characteristics between group A and group B were conducted. The relationship between various parameters and PSA-PFS was analyzed by the Kaplan-Meier method. A total of 26 patients (63.4%) were diagnosed with metastatic castration-resistant prostate cancer (mCRPC), and 38 cases (92.7%) had a Gleason score of 8-9. Bone metastasis, the predominant type of distant metastasis, occurred in 36 cases (87.8%). The skeletal and distant lymph node metastases mostly showed a dual positive uptake pattern for both PSMA and FDG (85.7% [24/28] and 81.8% [9/11]). 37.5% (3/8) of the metastases to organs showed FDG only positive uptake pattern. The serum levels of prostate specific antigen (PSA) in group A were significantly higher than those in group B (P=0.013). A total of 13 patients of special pathological classification (intraductal carcinoma and neuroendocrine differentiation) were all found to be in group A. Among the 41 cases, 16 were lost to follow-up. Of the 25 patients who completed follow-up, 9 patients, with a median PSA value of 104 ng/mL, experienced PSA progression, while the 16 other patients, with a median PSA of 0.34 ng/mL, did not incur any PSA progression. There was significant difference in the median PSA between patients showing PSA progression and those who did not show PSA progression (P<0.001). Kaplan-Meier survival analysis revealed that the median PSA-PFS of patients of specific pathological classifications was 7 months, which was shorter than the 16 months of the patients with typical prostate cancer, with the difference between the two groups being statistically meaningful (P=0.043). The median PSA-PFS for group A was 30 months. With more than half of the patients in the group not experiencing any PSA progression, group B did not reach the median PSA-PFS (P=0.645). Dual-tracer PET/CT imaging with 68Ga-PSMA and 18F-FDG commonly exhibits avidity for both tracers in mPCa. Serum PSA level is a reliable biomarker for predicting FDG-positive lesions. mPCa presented with intraductal carcinoma and neuroendocrine differentiation tends to exhibit FDG avidity and is more susceptible to PSA progression.

Advances in molecular imaging for early detection of lung cancer

Lung cancer remains the second most commonly diagnosed cancer globally and the leading cause of cancer-related deaths, a trend consistent in the United States as of 2023. One of the key reasons for the high mortality rate of lung cancer is its poor prognosis, with 75% of patients diagnosed at middle and advanced stages. Early detection of subclinical lung cancer, metastases, and their fibrotic stroma is crucial for enabling timely treatment, reducing reoccurrence, and stratifying patients. Current diagnostic methods, such as lung biopsy for patients with small nodules, are highly invasive and technically challenging. The radiological gold standard, computed tomography (CT), is associated with ionizing radiation. However, positron emission tomography (PET) and magnetic resonance imaging (MRI) have emerged as promising methodologies for lung cancer diagnosis. PET tracers with a variety of targeting mechanisms are currently under development in human trials. With advancements in hardware and software over the past decades, radiation-free MRI has been clinically and preclinically validated as an alternative to CT. Moreover, novel-targeted MRI contrast agents have been tested in animal models and show strong translational potential. In this review, we summarize the state-of-the-art progress in molecular imaging for the early detection of lung cancer and its potential biomarkers.

Detection rate of gastrin-releasing peptide receptor (GRPr) targeted tracers for positron emission tomography (PET) imaging in primary prostate cancer: a systematic review and meta-analysis.

The gastrin-releasing peptide receptor (GRPr) has gained recognition as a promising target for both diagnostic and therapeutic applications in a variety of human cancers. This study aims to explore the primary tumor detection capabilities of [68Ga] Ga-GRPr PET imaging, specifically in newly diagnosed intra-prostatic prostate cancer lesions (PCa). Following PRISMA-DTA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies) guidelines, a systematic literature search was conducted using the Medline, Embase, Scopus, and Web of Science databases. Data regarding patient characteristics and imaging procedure details-including the type of radiotracer used, administered activity, image acquisition time, scanner modality, criteria, and detection rate of index test-were extracted from the included studies. The pooled patient-and lesion-based detection rates, along with their corresponding 95% confidence intervals (CI), were calculated using a random effects model. The final analysis included 9 studies involving 291 patients and 350 intra-prostatic lesions with [68Ga] Ga-GRPr PET imaging in primary PCa. In per-patient-based analysis of [68Ga] Ga-GRPr PET imaging, the pooled detection rates of overall and patients with Gleason score ≥ 7 were 87.09% (95% CI 74.98-93.82) and 89.01% (95% CI 68.17-96.84), respectively. In per-lesion-based analysis, the pooled detection rate [68Ga] Ga-GRPr PET imaging was 78.54% (95% CI 69.8-85.29). The pooled detection rate mpMRI (multiparametric magnetic resonance imaging) in patient-based analysis was 91.85% (95% CI 80.12-96.92). The difference between the detection rates of the mpMRI and [68Ga] Ga-GRPr PET imaging was not statistically significant (OR 0.90, 95% CI 0.23-3.51). Our findings suggest that [68Ga] Ga-GRPr PET imaging has the potential as a diagnostic target for primary PCa. Future research is needed to determine the effectiveness of [68Ga] Ga-GRPr PET in delivering additional imaging data and guiding therapeutic decisions.

Fibroblast activation protein inhibitor positron emission tomography imaging in muscles of patients with idiopathic inflammatory myopathy.

Mesenchymal stromal cells in muscles participate in regeneration following muscle injury. This study explored the potential of [18F]fibroblast activation protein inhibitor (FAPI)-42 positron emission tomography (PET) targeting mesenchymal stromal cells to evaluate disease activity of idiopathic inflammatory myopathy (IIM). Patients with IIM (n = 26) were prospectively included and underwent [18F]FAPI-42 PET/CT and whole-body MRI between January 2023 and July 2023. Patients with malignancies were retrospectively included in the control group and only underwent [18F]FAPI-42 PET/CT (n = 28). [18F]FAPI-42 PET/CT images were evaluated using for avid-FAPI uptake and the target-to-background ratio (TBR). Whole-body MRI was evaluated for oedema, fatty infiltration, and atrophy in 42 muscles in the IIM group. The global FAPI- and MRI-derived parameters were calculated for each. . Clinical assessment of disease activity and muscle strength were collected. Patients with IIM had significantly higher global FAPI-avid muscle ratios (0.68 [interquartile range (IQR): 0.45, 0.79] vs 0.06 [IQR: 0, 0.11], p< 0.001) and global muscle TBR (2.26 [IQR: 1.71, 2.75] vs 1.23 [IQR: 1.02, 1.52], p< 0.001) compared with controls. In the IIM group, the median TBR was higher in muscles with oedema than in those without (2.44 [IQR: 1.46, 3.27] vs 1.31 [IQR: 0.95, 1.99], p< 0.001). Global FAPI-avid muscle ratios significantly correlated with global oedema score (r = 0.833), muscle strength (r=-0.649), serum creatine kinase (r = 0.456), and disease activity index (r = 0.495-0.621). Increased [18F]FAPI-42 uptake was associated with muscle oedema in IIM. FAPI-derived parameters correlated with IIM disease activity. [18F]FAPI-42 is a promising PET tracer for evaluating IIM disease activity.

68Ga]Ga-DOTAGA-Glu(FAPi)2 Shows Enhanced Tumor Uptake and Theranostic Potential in Preclinical PET Imaging.

The use of fibroblast activation protein inhibitors (FAPis) for positron emission tomography (PET) imaging in cancer has garnered significant interest in recent years, yielding promising results in preclinical and clinical settings. FAP is predominantly expressed in pathological conditions such as fibrosis and cancer, making it a compelling target. An optimized approach involves using FAPi homodimers as PET tracers, which enhance tumor uptake and retention, making them more effective candidates for therapy. Here, a UAMC-1110 inhibitor-based homodimer, DOTAGA-Glu(FAPi)2, was synthesized and radiolabeled with gallium-68, and its efficacy was evaluated in vivo for PET imaging in an endogenously FAP-expressing xenografted mouse model, U87MG. Notably, 45 min post-injection, the mean uptake of [68Ga]Ga-DOTAGA-Glu(FAPi)2 was 4.7 ± 0.5% ID/g in the tumor with low off-target accumulation. The ex vivo analysis of the FAP expression in the tumors confirmed the in vivo results. These findings highlight and confirm the tracer's potential for diagnostic imaging of cancer and as a theranostic companion.

Towards imaging the immune state of cancer by PET: Targeting legumain with 11C-labeled P1-Asn peptidomimetics carrying a cyano-warhead

PurposeM2-type tumor-associated macrophages (TAM) residing in the tumor microenvironment (TME) have been linked to tumor invasiveness, metastasis and poor prognosis. M2 TAMs suppress T cell activation, silencing the recognition of the cancer by the immune system. Targeting TAMs in anti-cancer therapy may support the immune system and immune-checkpoint inhibitor therapies to fight the cancer cells. We aimed to develop a PET tracer for the imaging of M2 TAM infiltration of cancer, using activated legumain as the imaging target. Basic proceduresTwo P1-mimicking inhibitors with a cyano-warhead were labeled with carbon-11 and evaluated in vitro and in vivo with a CT26 tumor mouse model. Target expression and activity were quantified from RT-qPCR and in vitro substrate conversion, respectively. The co-localization of legumain and TAMs was assessed by fluorescence microscopy. The two tracers were evaluated by PET with subsequent biodistribution analysis with the dissected tissues. Parent-to-total radioactivity in plasma was determined at several time points after i.v. tracer injection, using reverse phase radio-UPLC. Main findingsLegumain displayed a target density of 40.7 ± 19.1 pmol per mg total protein in tumor lysate (n = 4) with high substrate conversion and colocalization with M2 macrophages in the tumor periphery. [11C]1 and [11C]2 were synthesized with >95 % radiochemical purity and 12.9–382.2 GBq/μmol molar activity at the end of synthesis. We observed heterogeneous tumor accumulation in in vitro autoradiography and PET for both tracers. However, excess unlabeled 1 or 2 did not compete with tracer accumulation. Both [11C]1 and [11C]2 were rapidly metabolized to a polar radiometabolite in vivo. Principal conclusionsThe legumain tracers [11C]1 and [11C]2, synthesized with high radiochemical purity and molar activity, accumulate in the legumain-positive CT26 tumor in vivo. However, the lack of competition by excess compound questions their specificity. Both tracers are rapidly metabolized in vivo, requiring structural modifications towards more stable tracers for further investigations.

Translational Preclinical PET Imaging and Metabolic Evaluation of a New Cannabinoid 2 Receptor (CB2R) Radioligand, (Z)-N-(3-(2-(2-[18F]Fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide.

We have previously developed seven fluorinated analogues of A-836339 as new PET tracers for cannabinoid type 2 receptor (CB2R) imaging, among which (Z)-N-(3-(2-(2-[18F]fluoroethoxy)ethyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethylcyclopropane-1-carboxamide ([18F]FC0324) displayed high affinity and selectivity for CB2R in healthy rats. In the present study, we have further evaluated the imaging and metabolic properties of [18F]FC0324 in a rat model of human CB2R overexpression in the brain (AAV-hCB2) and in non-human primates (NHPs). Autoradiography with AAV-hCB2 rat brain sections exhibited a signal of [18F]FC0324 8-fold higher in the ipsilateral region than in the contralateral region. Blocking with NE40, a CB2R-specific agonist, resulted in a 91% decrease in the radioactivity. PET experiments showed a signal 7-fold higher in the ipsilateral region, and the specificity of [18F]FC0324 for hCB2R in vivo was confirmed by the 80% decrease after blocking with NE40. In NHPs, brain time-activity curves displayed a fast and homogeneous distribution followed by a rapid washout, in accordance with the low amount of CB2Rs in healthy brain. Whole-body PET-CT suggested a high and specific uptake of the radiotracer in the spleen, a CB2R-rich organ, and in the organs involved in metabolism and excretion, with a low bone uptake. In vitro metabolism with monkey liver microsomes (MLMs) led to the formation of six main hydroxylated metabolites of FC0324. Five of them were produced by human liver microsomes, being much less active than MLMs. In vivo, in NHPs, the main radiometabolite was likely to result from further oxidation of hydroxylated compounds, and parent [18F]FC0324 accounted for 8 ± 3% of plasma radioactivity (at 120 min p.i.) with a low level of potential interfering radiometabolites. Furthermore, this metabolism should be significantly reduced in humans due to species differences. In conclusion, [18F]FC0324 appears to be a promising candidate for further human studies with suitable kinetics, selectivity, and metabolic profile for CB2R PET imaging.

Development of a Novel Peptide-Based PET Tracer [68Ga]Ga-DOTA-BP1 for BCMA Detection in Multiple Myeloma.

B-cell maturation antigen (BCMA) has emerged as a promising tumor marker for the diagnosis and treatment of multiple myeloma. The noninvasive and rapid detection of BCMA expression in vivo provides significant value in screening and evaluating multiple myeloma patients receiving BCMA-targeted therapy. We identified the BCMA-targeting peptide BP1 from a one-bead-one-compound (OBOC) peptide library using a high-throughput microarray strategy. The BCMA-targeting specificity and affinity of BP1 were assessed by surface plasmon resonance imaging (SPRi), flow cytometry, and confocal imaging. BCMA-positive (H929) and BCMA-negative (K562) subcutaneous tumor models were established and labeled with 68Ga for BP1, followed by PET imaging and biodistribution studies. PET imaging demonstrated that 68Ga-labeled BP1 has significant specific uptake in multiple myeloma, enabling rapid identification of BCMA expression and precise delineation of the disease. Thus, BP1 represents an ideal candidate for multiple myeloma imaging.

Discovery of a highly specific radiolabeled antibody targeting B-cell maturation antigen: Applications in PET imaging of multiple myeloma.

Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM. Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential. The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells hada total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430. Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.