Synthesis and preclinical evaluation of a novel probe [18F]AlF-NOTA-IPB-GPC3P for PET imaging of GPC3 positive tumor.

Glypican-3 (GPC3) is markedly overexpressed in hepatocellular carcinoma (HCC) and not expressed in normal liver tissues. In this study, a novel peptide PET imaging agent ([18F]AlF-NOTA-IPB-GPC3P) was developed to target GPC3 expressed in tumors. The overall radiochemical yield of [18F]AlF-NOTA-IPB-GPC3P was 10-15 %, and its lipophilicity, expressed as the logD value at a pH of 7.4, was -1.18 ± 0.06 (n = 3). Compared to the previously reported tracer [18F]AlF-GP2633, [18F]AlF-NOTA-IPB-GPC3P exhibited higher cellular uptake (15.13 vs 5.96) and internalized rate (80.63 % vs 35.93 %) in Huh7 cells at 120 min. Micro-PET/CT and biodistribution studies further demonstrated that [18F]AlF-NOTA-IPB-GPC3P exhibited significantly increased tumor uptake and prolonged tumor residence in Huh7 tumors compared to [18F]AlF-GP2633 (4.66 ± 0.22 % ID/g vs 0.72 ± 0.09 % ID/g at 60 min, p < 0.001; 5.05 ± 0.23 % ID/g vs 0.35 ± 0.08 % ID/g at 120 min, p < 0.001, respectively). Furthermore, the tumor-to-organ ratios of [18F]AlF-NOTA-IPB-GPC3P surpassed those of [18F]AlF-GP2633. Our results support the utilization of [18F]AlF-NOTA-IPB-GPC3P as a PET imaging agent targeting the GPC3 receptor for tumor detection.

Synthesis and Evaluation of [18F]AlF-NOTA-c-DVAP: A Novel PET Probe for Imaging GRP78 in Cancer.

GRP78, a member of the HSP70 superfamily, is an endoplasmic reticulum chaperone protein overexpressed in various cancers, making it a promising target for cancer imaging and therapy. Positron emission tomography (PET) imaging offers unique advantages in real time, noninvasive tumor imaging, rendering it a suitable tool for targeting GRP78 in tumor imaging to guide targeted therapy. Several studies have reported successful tumor imaging using PET probes targeting GRP78. However, existing PET probes face challenges such as low tumor uptake, inadequate in vivo distribution, and high abdominal background signal. Therefore, this study introduces a novel peptide PET probe, [18F]AlF-NOTA-c-DVAP, for targeted tumor imaging of GRP78. [18F]AlF-NOTA-c-DVAP was radiolabeled with fluoride-18 using the aluminum-[18F]fluoride ([18F]AlF) method. The study assessed the partition coefficients, stability in vitro, and metabolic stability of [18F]AlF-NOTA-c-DVAP. Micro-PET imaging, pharmacokinetic analysis, and biodistribution studies were carried out in tumor-bearing mice to evaluate the probe's performance. Docking studies and pharmacokinetic analyses of [18F]AlF-NOTA-c-DVAP were also performed. Immunohistochemical and immunofluorescence analyses were conducted to confirm GRP78 expression in tumor tissues. The probe's binding affinity to GRP78 was analyzed by molecular docking simulation. [18F]AlF-NOTA-c-DVAP was radiolabeled in just 25 min with a high yield of 51 ± 16%, a radiochemical purity of 99%, and molar activity within the range of 20-50 GBq/µmol. [18F]AlF-NOTA-c-DVAP demonstrated high stability in vitro and in vivo, with a logD value of -3.41 ± 0.03. Dynamic PET imaging of [18F]AlF-NOTA-c-DVAP in tumors showed rapid uptake and sustained retention, with minimal background uptake. Biodistribution studies revealed rapid blood clearance and excretion through the kidneys following a single-compartment reversible metabolic model. In PET imaging, the T/M ratios for A549 tumors (high GRP78 expression), MDA-MB-231 tumors (medium expression), and HepG2 tumors (low expression) at 60 min postintravenous injection were 10.48 ± 1.39, 6.25 ± 0.47, and 3.15 ± 1.15% ID/g, respectively, indicating a positive correlation with GRP78 expression. This study demonstrates the feasibility of using [18F]AlF-NOTA-c-DVAP as a PET tracer for imaging GRP78 in tumors. The probe shows promising results in terms of stability, specificity, and tumor targeting. Further research may explore the clinical utility and potential therapeutic applications of this PET tracer for cancer diagnosis.

Synthesis and preclinical evaluation of a novel molecular probe [18F]AlF-NOTA-PEG2-Asp2-PDL1P for PET imaging of PD-L1 positive tumor.

Immunotherapy has brought great benefits to cancer patients, but only some patients benefit from it. Noninvasive, real-time and dynamic monitoring of the effectiveness of immunotherapy through PET imaging may provide assistance for the treatment plan of immunotherapy. In this study, we designed and synthesized a new targeted PD-L1 peptide NOTA-PEG2-Asp2-PDL1P, which was labeled with nuclide 18F to obtain a new imaging agent [18F]AlF-NOTA-PEG2-Asp2-PDL1P. The total radiochemical yield of [18F]AlF-NOTA-PEG2-Asp2-PDL1P was 13.7 % (Uncorrected radiochemical yield, n > 5). [18F]AlF-NOTA-PEG2-Asp2-PDL1P achieved high radiochemical purity (>95 %) with a molar activity more than 51.2 GBq/µmol. [18F]AlF-NOTA-PEG2-Asp2-PDL1P exhibited good hydrophilicity and had good stability both in vivo and in vitro, it can specifically targets B16F10 tumor with PD-L1 expression, and had a relatively high retention in tumor, a relatively fast clearance in vivo and a higher tumor-to-non-target ratio, all of which could make [18F]AlF-NOTA-PEG2-Asp2-PDL1P a potential tracer for PD-L1 prediction before clinical immunotherapy.

Synthesis and preclinical evaluation of a novel PET/fluorescence dual-modality probe targeting fibroblast activation protein.

Early diagnosis and precise surgical intervention are crucial for cancer patients. We aimed to develop a novel positron emission tomography (PET)/fluorescence dual-modality probe for preoperative diagnosis, intraoperative guidance, and postoperative monitoring of fibroblast activation protein (FAP)-positive tumors. FAPI-FAM was synthesized and labeled with gallium-68. [68Ga]Ga-FAPI-FAM showed favorable in vivo and in vitro characteristics, specific binding affinity, and excellent tumor accumulation in FAP-positive cells and mice xenografts. Excellent tumor-to-background contrast was found owing to high tumor uptake, prolonged retention, and rapid renal clearance of [68Ga]Ga-FAPI-FAM. Moreover, a specific fluorescence signal was detected in FAP-positive tumors during ex vivo fluorescence imaging, demonstrating the feasibility of whole-body tumor detection and intraoperative tumor delineation.

Formulation and Preclinical Testing of Tc-99m-Labeled HYNIC-Glc-FAPT as a FAP-Targeting Tumor Radiotracer.

Molecular imaging and targeted radiotherapy with radiolabeled fibroblast activation protein inhibitor (FAPI) targeting peptide probes hold great potential for enhancing the clinical management of patients with FAP-expressing cancers. However, the high cost of PET probes has prompted us to search for new FAP-targeting single-photon imaging agents. In this study, HYNIC-Glc-FAPT is synthesized and radiolabeled with technetium-99m using tricine/EDDA or dimer tricine as coligands to produce [99mTc]Tc-tricine/EDDA-HYNIC-Glc-FAPT and [99mTc]Tc-tricine(2)-HYNIC-Glc-FAPT. Both [99mTc]Tc-tricine/EDDA-HYNIC-Glc-FAPT and [99mTc]Tc-tricine(2)-HYNIC-Glc-FAPT were effectively synthesized with an excellent radiochemistry yield (both >97%, n = 6) in a single-step technique, and their stability in PBS and human serum was satisfactory. Compared to [99mTc]Tc-tricine(2)-HYNIC-Glc-FAPT, [99mTc]Tc-tricine/EDDA-HYNIC-Glc-FAPT exhibited a more hydrophilic nature with a log P of -3.53 ± 0.12. In vitro cellular uptake and blocking assays, internalization, efflux experiments, and affinity experiments all suggested a mechanism with high FAP-specificity and affinity. SPECT imaging and biodistribution of [99mTc]Tc-tricine/EDDA-HYNIC-Glc-FAPT demonstrated sustained high tumor uptake in BALB/c nude mice bearing U87MG tumors for 6 h. It demonstrated a long-range retention characteristic and more rapid clearance ability from nontarget organs. Collectively, we successfully synthesized [99mTc]Tc-tricine/EDDA-HYNIC-Glc-FAPT and [99mTc]Tc-tricine(2)-HYNIC-Glc-FAPT, and the excellent targeting properties of [99mTc]Tc-tricine/EDDA-HYNIC-Glc-FAPT suggest a potential diagnostic value in future clinical studies for advanced-stage FAP-expressing malignancies, especially in prognostic evaluation of tumors for it low price and convenient source.

PET/CT imaging fibroblast activation protein in initial colorectal cancer: compared to 18 F-FDG PET/CT.

OBJECTIVE: In this study, the potential advantage of FAPI over 18 F-labelled deoxyglucose ( 18 F-FDG) in evaluation of the initial staging colorectal cancer (CRC) was investigated. MATERIALS AND METHODS: Thirty-two patients with histopathologically confirmed primary CRC were included in our study. They all underwent both 18 F-FDG and FAPI PET/CT. Lesion detectability and tracer uptakes, mainly quantified by maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR), were compared for paired lesions between both modalities using the Wilcoxon signed-rank test and paired t-test. RESULTS: Thirty-five CRC lesions in 32 patients were diagnosed. The sensitivity of FAPI PET/CT in diagnosis of the CRC lesions was 100% while 93.8% of 18 F-FDG PET/CT. FAPI and 18 F-FDG had a similar uptake in CRC lesion (mean SUVmax: 14.3 ±â€…8.6 vs. 15.4 ±â€…9.8, P  = 0.604), but lesions contained mucus and/or signet-ring cell carcinoma seemed to have a trend of higher FAPI uptake although there was no statistical difference (mean SUVmax: 12.7 ±â€…5.6 vs. 8.5 ±â€…4.1, P  = 0.152) and higher TBR (13.4 ±â€…6.2 vs. 4.9 ±â€…2.2, P  = 0.004) than those of 18 F-FDG. For regional lymph node metastases, both FAPI and FDG PET/CTs showed high sensitivity (7/8 vs. 7/8), specificity (7/8 vs. 6/8) and accuracy (14/16 vs. 13/16) (all P  > 0.05). For distant metastasis, FAPI PET/CT depicted more positive lesions in distant lymph node (46 vs. 26), liver (13 vs. 7) and peritoneum (107 vs. 45) than 18 F-FDG PET/CT. FAPI PET/CT also had a higher peritoneal cancer index score (median 11 vs 4; P  < 0.001) than 18 F-FDG PET/CT in evaluation of peritoneal metastases. CONCLUSION: FAPI PET/CT showed high sensitivity in detection of primary CRC and superiority to 18 F-FDG PET/CT in detection of metastases to distant lymph node, liver and peritoneum.

Radiosynthesis, preclinical evaluation and pilot clinical PET imaging study of a 18F-labeled tracer targeting fibroblast activation protein.

Fibroblast activation protein (FAP) is a promising molecular target for imaging in various types of cancers. Several 18F-labeled FAP inhibitor (FAPI) tracers have been evaluated in clinical study. However, these tracers display high physiological uptake in gallbladder and bile duct system. To overcome the limitation, we herein designed a novel radiotracer named 18F-FAPTG. 18F-FAPTG was produced with a non-decay-corrected radiochemical yield of 24.0 ± 6.0% and 22.0 ± 7.0% for manual and automatic synthesis, respectively. 18F-FAPTG exhibited high hydrophilicity and stability in vitro. The studies of cellular uptake, internalization, efflux properties and competitive binding to FAP of 18F-FAPTG indicated that the tracer showed high specificity, rapid internalization and low cellular efflux in FAP-positive cells. Biodistribution studies and microPET in mice bearing FAP-positive xenografts demonstrated extremely low uptake in the majority of other organs and main excretion of 18F-FAPTG through the urinary system. Furthermore, compared to 18F-FAPI-42, 18F-FAPTG showed significantly lower uptake in gallbladder, higher tumor uptake and longer tumor retention. In the pilot clinical study, 18F-FAPTG PET/CT demonstrated favorable tumor-to-background ratios in most organs and clearly displayed the malignant lesions. Our findings indicated that 18F-FAPTG had an advantage over 18F-FAPI-42 in PET imaging for cancers located in gallbladder the bile duct system. Thus, 18F-FAPTG could be an alternative to the currently available FAPI tracers.

A comparative 18F-FDG and an anti-PD-L1 probe PET/CT imaging of implant-associated Staphylococcus aureus osteomyelitis.

Background: Early and accurate diagnosis of infection-induced osteomyelitis, which often involves increased PD-L1 expression, is crucial for better treatment outcomes. Radiolabeled anti-PD-L1 nuclear imaging allows for sensitive and non-invasive whole-body assessments of PD-L1 expression. This study aimed to compare the efficacy of 18F-FDG and an 18F-labeled PD-L1-binding peptide probe (18F-PD-L1P) in PET imaging of implant-associated Staphylococcus aureus osteomyelitis (IAOM). Methods: In this study, we synthesized an anti-PD-L1 probe and compared its efficacy with 18F-FDG and 18F-PD-L1P in PET imaging of implant-associated Staphylococcus aureus osteomyelitis (IAOM). The %ID/g ratios (i.e., radioactivity ratios between the infected and non-infected sides) of both probes were evaluated for sensitivity and accuracy in post-infected 7-day tibias and post-infected 21 days, and the intensity of 18F-PD-L1P uptake was compared with pathological changes measured by PD-L1 immunohistochemistry (IHC). Results: Compared with 18F-FDG, 18F-PDL1P demonstrated higher %ID/g ratios for both post-infected 7-day tibias (P=0.001) and post-infected 21 days (P=0.028). The intensity of 18F-PD-L1P uptake reflected the pathological changes of osteomyelitic bones. In comparison to 18F-FDG, 18F-PDL1P provides earlier and more sensitive detection of osteomyelitis caused by S. aureus. Conclusion: Our findings suggest that the 18F-PDL1P probe is a promising tool for the early and accurate detection of osteomyelitis caused by S. aureus.

Noninvasive imaging of FAP expression using positron emission tomography: A comparative evaluation of a [18F]-labeled glycopeptide-containing FAPI with [18F]FAPI-42.

PURPOSE: Research on fibroblast activating protein (FAP)-targeting inhibitor (FAPI) has become an important focus for cancer imaging and radiotherapy. Quinoline-based tracers [68 Ga]FAPI-04 and [18F]FAPI-42 have been widely used for positron emission tomography (PET) imaging of most tumors. However, there exist some limitations of these tracers with high uptake in biliary duct system and unstable uptake in pancreas, unsuitable for abdominal tumors PET imaging. Here we developed a [18F]-labeled glycopeptide-containing FAPI tracer (named [18F]FAPT) for PET imaging of FAP in cancers. METHODS: [18F]FAPT was synthesized manually and automatically. The competitive binding to FAP, cellular internalization, and efflux characteristics were examined in vitro using A549-FAP cells. Dynamic MicroPET and biodistribution studies of [18F]FAPT were then conducted in A549-FAP and U87MG xenograft tumor mouse models compared with [18F]FAPI-42. Five healthy volunteers and three patients with cancer underwent [18F]FAPT PET/CT. RESULTS: Preclinical and clinical studies showed specific binding of [18F]FAPT to FAP and favorable pharmacokinetic properties with better hydrophilicity, lower uptake in biliary duct system, higher tumor uptake and longer tumor retention compared with [18F]FAPI-42. The biodistribution of [18F]FAPT in healthy volunteers and patients with cancer displayed low uptake in most normal tissues except for pancreas, thyroid and salivary gland, which could contribute to high tumor-to-background ratios in most cancers. CONCLUSION: [18F]FAPT is better PET tracer than [18F]FAPI-42 for imaging of biliary duct system cancer, potentially providing a tool to examine FAP expression in most cancers with high tumor-to-background ratios.

A Comparative Study of 18F-FAPI-42 and 18F-FDG PET/CT for Evaluating Acute Kidney Injury in Cancer Patients.

PURPOSE: Compare the value of imaging using positron 18F-labeled fibroblast activation protein inhibitor-42 (18F-FAPI-42) and 18F-labeled deoxyglucose (18F-FDG) for assessment of AKI. PROCEDURES: This study analyzed cancer patients who received 18F-FAPI-42 and 18F-FDG PET/CT imaging. Eight patients had AKI with bilateral ureteral obstruction (BUO), eight had BUO (CKD1-2) with no acute kidney disease (AKD), and eight had no ureteral obstruction (UO) with normal renal function. The average standardized uptake value (SUVave) of the renal parenchyma (RP-SUVave), the blood pool SUVave (B- SUVave), SUVave in the highest region of the renal collective system (RCS-SUVave), and the highest serum creatinine level (top SCr) were recorded. RESULTS: The 18F-FAPI-42 and 18F-FDG results showed that radiotracer of renal parenchyma was more concentrated in the AKI group than in the other two groups, whereas the RP-SUVave from 18F-FAPI-42 was higher than that from 18F-FDG in the AKI group (all P < 0.05). 18F-FAPI-42 imaging in the AKI group showed uptake by the renal parenchyma with a diffuse increase, but very little radiotracer in the renal collecting system, similar to a "super kidney scan." The renal parenchyma also had an increase of SUVave, with accumulation of radiotracer in the renal collecting system. AKI was more severe when a patient had a "super kidney scan" in both kidneys (P < 0.05). The B-SUVave level was higher in the AKI group than in the other two groups in 18F-FAPI-42 (both P < 0.05). CONCLUSIONS: 18F-FAPI-42 imaging had higher RP-SUVave than 18F-FDG imaging in cancer patients who had BUO with AKI. An increased renal parenchyma uptake in both kidneys and low radiotracer distribution in the collecting system suggest more severe AKI.

Superiority of [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT to [18F]FDG PET/CT in delineating the primary tumor and peritoneal metastasis in initial gastric cancer.

OBJECTIVE: This study aimed to compare [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT with [18F]FDG PET/CT in the evaluation of initial gastric cancer. METHODS: We retrospectively compared [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT with [18F]FDG PET/CT in patients with initial gastric cancer from September 2020 to March 2021. Lesion detectability and the uptake of lesions quantified by the maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR) were compared between the two modalities using the Wilcoxon signed-rank test, Mann-Whitney U test, and McNemar's chi-square test. RESULTS: A total of 61 patients (37 males, aged 23-81 years) were included, of which 22 underwent radical gastrectomy. For primary lesions, higher uptake of [68Ga]Ga-FAPI-04/[18F]FAPI-42 was observed compared to [18F]FDG (median SUVmax, 14.60 vs 4.35, p < 0.001), resulting in higher positive detection using [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT than [18F]FDG PET/CT (95.1% vs 73.8%, p < 0.001), particularly for tumors with signet-ring cell carcinoma (SRCC) (96.4% vs 57.1%, p < 0.001). [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT detected more positive lymph nodes than [18F]FDG PET/CT (637 vs 407). However, both modalities underestimated N staging compared to pathological N staging. [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT showed a higher sensitivity (92.3% vs 53.8%, p = 0.002) and peritoneal cancer index score (18 vs 3, p < 0.001) in peritoneum metastasis and other suspect metastases compared to [18F]FDG PET/CT. CONCLUSION: Our findings indicate that [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT outperformed [18F]FDG PET/CT in the evaluation of primary tumors with SRCC and peritoneum metastasis in initial gastric cancer. However, no clinically useful improvement was seen in N staging. KEY POINTS: • The uptake of [68Ga]Ga-FAPI-04/[18F]FAPI-42 in primary tumor and metastasis was intensely higher than that of [18F]FDG (p < 0.001) in 61 patients with initial gastric cancer. • [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT had a higher sensitivity detection in primary tumors (95.1% vs 73.8%, p < 0.001) and peritoneal metastases (92.3% vs 53.8%, p = 0.002) than [18F]FDG PET/CT. • [68Ga]Ga-FAPI-04/[18F]FAPI-42 PET/CT depicted more positive lymph nodes than [18F]FDG PET/CT (637 vs 407); however, both underestimated N staging compared to pathological N staging.

Synthesis and biological evaluation of Al[18F]-NOTA-IPB-PDL1P as a molecular probe for PET imaging of PD-L1 positive tumors.

PD-L1 is widely expressed in a variety of tumors, including NSCLC, melanoma, renal cell carcinoma, gastric cancer, hepatocellular as well as cutaneous and various leukemias, multiple myeloma and so on. Herein, we designed a novel peptide imaging agent (Al[18F]-NOTA-IPB-PDL1P) that specifically targets PD-L1 expressed in tumors. The overall radiochemical yield of Al[18F]-NOTA-IPB-PDL1P from 18F- was 10-15% (corrected radiochemical yield) within 20 min and the radiochemical purity of Al[18F]-NOTA-IPB-PDL1P was > 95% with a molar activity of 44.4-64.8 GBq/µmol. The lipophilicity logP value of Al[18F]-NOTA-IPB-PDL1P at pH 7.4 was -1.768 ±â€¯0.007 (n = 3). In the cellular uptake experiment, both HCT116 and PC3 cells dispalyed high uptake to Al[18F]-NOTA-IPB-PDL1P. The results of biodistribution showed that the uptake of Al[18F]-NOTA-IPB-PDL1P was high in kidneys, gall bladder and lung, and low in muscle and brain. In vivo micro PET studies, both HCT116 and PC3 tumors displayed high uptake for Al[18F]-NOTA-IPB-PDL1P, the tumor/muscle (T/M) radio was 2.93 and 3.57 respectively at 120 min. All the results indicate that Al[18F]-NOTA-IPB-PDL1P may have potential to be a PET imaging agent of tumors with high PD-L1 expression.

Preclinical evaluation and pilot clinical study of [18F]AlF-labeled FAPI-tracer for PET imaging of cancer associated fibroblasts.

In recent years, fibroblast activation protein (FAP) has emerged as an attractive target for the diagnosis and radiotherapy of cancers using FAP-specific radioligands. Herein, we aimed to design a novel 18F-labeled FAP tracer ([18F]AlF-P-FAPI) for FAP imaging and evaluated its potential for clinical application. The [18F]AlF-P-FAPI novel tracer was prepared in an automated manner within 42 min with a non-decay corrected radiochemical yield of 32 ± 6% (n = 8). Among A549-FAP cells, [18F]AlF-P-FAPI demonstrated specific uptake, rapid internalization, and low cellular efflux. Compared to the patent tracer [18F]FAPI-42, [18F]AlF-P-FAPI exhibited lower levels of cellular efflux in the A549-FAP cells and higher stability in vivo. Micro-PET imaging in the A549-FAP tumor model indicated higher specific tumor uptake of [18F]AlF-P-FAPI (7.0 ± 1.0% ID/g) compared to patent tracers [18F]FAPI-42 (3.2 ± 0.6% ID/g) and [68Ga]Ga-FAPI-04 (2.7 ± 0.5% ID/g). Furthermore, in an initial diagnostic application in a patient with nasopharyngeal cancer, [18F]AlF-P-FAPI and [18F]FDG PET/CT showed comparable results for both primary tumors and lymph node metastases. These results suggest that [18F]AlF-P-FAPI can be conveniently prepared, with promising characteristics in the preclinical evaluation. The feasibility of FAP imaging was demonstrated using PET studies.

Comparison of 68Ga-FAPI and 18F-FDG PET/CT in the Evaluation of Advanced Lung Cancer.

Background Gallium 68 (68Ga)-labeled fibroblast-activation protein inhibitor (FAPI) has recently been introduced as a promising tumor imaging agent. Purpose To compare 68Ga-FAPI PET/CT with fluorine 18 (18F)-labeled fluorodeoxyglucose (FDG) PET/CT in evaluating lung cancer. Materials and Methods In this prospective study conducted from September 2020 to February 2021, images from participants with lung cancer who underwent both 68Ga-FAPI and 18F-FDG PET/CT examinations were analyzed. The tracer uptakes, quantified by maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR), were compared for paired positive lesions between both modalities using the paired t test or Wilcoxon signed-rank test. Results Thirty-four participants (median age, 64 years [interquartile range: 46-80 years]; 20 men) were evaluated. From visual evaluation, 68Ga-FAPI PET/CT and 18F-FDG PET/CT showed similar performance in the delineation of primary tumors and detection of suspected metastases in the lungs, liver, and adrenal glands. The metabolic tumor volume in primary and recurrent lung tumors showed no difference between modalities (mean: 11.6 vs 10.8, respectively; P = .68). However, compared with 18F-FDG PET/CT, 68Ga-FAPI PET/CT depicted more suspected metastases in lymph nodes (356 vs 320), brain (23 vs 10), bone (109 vs 91), and pleura (66 vs 35). From semiquantitative evaluation, the SUVmax and TBR of primary or recurrent tumors, positive lymph nodes, bone lesions, and pleural lesions at 68Ga-FAPI PET/CT were all higher than those at 18F-FDG PET/CT (all P < .01). Although SUVmax of 68Ga-FAPI and 18F-FDG in brain metastases were not different (mean SUVmax: 9.0 vs 7.4, P = .32), TBR was higher with 68Ga-FAPI than with 18F-FDG (mean: 314.4 vs 1.0, P = .02). Conclusion Gallium 68-labeled fibroblast-activation protein inhibitor PET/CT may outperform fluorine 18-labeled fluorodeoxyglucose PET/CT in staging lung cancer, particularly in the detection of metastasis to the brain, lymph nodes, bone, and pleura. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Jacobson and Van den Abbeele in this issue.

[18F]FAPI-42 PET imaging in cancer patients: optimal acquisition time, biodistribution, and comparison with [68Ga]Ga-FAPI-04.

PURPOSE: [18F]FAPI-42 is a new fibroblast activation protein (FAP)-specific tracer used for cancer imaging. Here, we describe the optimal acquisition time and in vivo evaluation of [18F]FAPI-42 and compared intra-individual biodistribution, tumor uptake, and detection ability to [68Ga]Ga-FAPI-04. METHODS: A total of 22 patients with various types of cancer received [18F]FAPI-42 whole-body positron emission tomography/computed tomography (PET/CT). Among them, 4 patients underwent PET/CT scans, including an early dynamic 20-min, static 1-h, and static 2-h scans. The in vivo biodistribution in normal organs and tumor uptake were semiquantitatively evaluated using the standardized uptake value (SUV) and tumor-to-background ratio (TBR). Furthermore, both [18F]FAPI-42 and [68Ga]Ga-FAPI-04 PET/CT were performed in 12 patients to compare biodistribution, tumor uptake, and tumor detection ability. RESULTS: [18F]FAPI-42 uptake in the tumors was rapid and reached a high level with an average SUVmax of 15.8 at 18 min, which stayed at a similarly high level to 2 h. The optimal image acquisition time for [18F]FAPI-42 was determined to be 1 h postinjection. For tumor detection, [18F]FAPI-42 had a high uptake and could be clearly visualized in the lesions. Compared to [68Ga]Ga-FAPI-04, [18F]FAPI-42 had the same detectability for 144 positive lesions. In addition, [18F]FAPI-42 showed a higher SUVmax in liver and bone lesions (P < 0.05) and higher TBRs in liver, bone, lymph node, pleura, and peritoneal lesions (all P < 0.05). CONCLUSION: The present study demonstrates that the optimal image acquisition time of [18F]FAPI-42 is 1 h postinjection and that [18F]FAPI-42 exhibits comparable lesion detectability to [68Ga]Ga-FAPI-04. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100045757).

Novel PET/CT tracers for targeted imaging of membrane receptors to evaluate cardiomyocyte apoptosis and tissue repair process in a rat model of myocardial infarction.

The purpose of this study was to employ novel tracers PET imaging approach to define the time course and intensity of myocardial repair after apoptosis and to correlate the imaging signal to immunohistochemical staining in myocardial infarction (MI). We designed novel αVß3-targeted and radio-functionalized tracers for detection of apoptosis in H9C2 cells and myocardial tissue. MI rats were imaged with [18F]FDG, [18F]ANP-Cin or [18F]ANP-RGD2 using a small-animal PET/CT device. Rats were sacrificed, and tissue samples from viable and injured myocardial areas were sectioned for TUNEL assay and histology. The uncorrected radiochemical yield of [18F]ANP-Cin and [18F]ANP-RGD2 were 41.3 ± 5.4% and 21.17 ± 4.7%, respectively. Two tracers meet many criteria for cardiac imaging, including high stability, high binding, no toxicity, fast renal clearance and excellent biodistribution in rat models. The uptake of [18F]ANP-Cin was significantly higher on the 1st and 3rd day than the 7th or 28th day after MI induction, a timeframe associated with increased cardiomyocyte apoptosis. Higher uptake of [18F]ANP-Cin was observed in MI rats than in N-acetylcysteine (NAC)-treated rats on the 3rd days. In contrast with [18F]ANP-Cin, no hot-spots was observed with [18F]ANP-RGD2 on the 1st day and more hot-spots was observed from the 3rd day to the 7th day, then less on the 28th days in the high apoptotic site. There was no uptake of [18F]FDG in or around the apoptotic region. On the 7th day the uptake of [18F]ANP-RGD2 was higher in NAC-treated rats than MI rats. [18F]ANP-Cin and [18F]ANP-RGD2 are superior to [18F]FDG for PET/CT imaging for evaluation of cardiomyocyte apoptosis and tissue repair processes in the MI rats.

Cell death PET/CT imaging of rat hepatic fibrosis with 18F-labeled small molecule tracer.

PURPOSE: To evaluate the potential feasibility of Al[18F]F-1,4,7-triazacyclononane-1,4,7-triaceticacid (NOTA)-tripolyethylene glycol (PEG3)-Duramycin (Al[18F]F-NOTA-PEG3-Duramycin) positron emission tomography (PET) for imaging of rat hepatic fibrosis. PROCEDURES: Hepatic fibrosis rat models were injected with thioacetamide (TAA), control rats received saline (n = 12 per group). Rats in the two groups underwent PET imaging using Al[18F]F-NOTA-PEG3-Duramycin and [18F]FDG at multiple time points (2, 4, 6, and 8 weeks after TAA or saline treatment). Between-group differences in the apoptosis rate, fibrotic activity, and liver uptake of Al[18F]F-NOTA-PEG3-Duramycin or [18F]FDG were assessed using Student's t-test. Imaging results were cross-validated using histopathology detection and Pearson's correlation test was used to assess the association relationships between radioactive uptake value and quantified histopathological data. RESULTS: Compared with control group at multiple time points, each TAA group showed a higher radioactive liver uptake of Al[18F]F-NOTA-PEG3-Duramycin (each P < 0.05). Furthermore, the increase in the liver uptake of Al[18F]F-NOTA-PEG3-Duramycin was proportional to the progression of fibrosis (R2 = 0.8846, P < 0.001) and apoptosis rate (R2 = 0.9208, P < 0.001) in the TAA group. Meanwhile, there were also between-group differences in [18F]FDG uptake in each phase (P < 0.05), however, no relationship between [18F]FDG uptake and the fibrotic activity was observed. CONCLUSIONS: Al[18F]F-NOTA-PEG3-Duramycin PET/CT could be applied to monitor the progression of liver fibrosis, whereas [18F]FDG PET/CT could not. Implications of this work for noninvasive diagnosis of liver fibrosis, assessment of fibrotic activity, and evaluation of antifibrotic therapy are expected.

Biological Evaluation of [18F]AlF-NOTA-NSC-GLU as a Positron Emission Tomography Tracer for Hepatocellular Carcinoma.

Purpose: N-(2-[18F]fluoropropionyl)-L-glutamate ([18F]FPGLU) for hepatocellular carcinoma (HCC) imaging has been performed in our previous studies, but its radiosynthesis method and stability in vivo need to be improved. Hence, we evaluated the synthesis and biological properties of a simple [18F]-labeled glutamate analog, [18F]AlF-1,4,7-triazacyclononane-1,4,7-triacetic-acid-2-S-(4-isothiocyanatobenzyl)-l-glutamate ([18F]AlF-NOTA-NSC-GLU), for HCC imaging. Procedures: [18F]AlF-NOTA-NSC-GLU was synthesized via a one-step reaction sequence from NOTA-NSC-GLU. In order to investigate the imaging value of [18F]AlF-NOTA-NSC-GLU in HCC, we conducted positron emission tomography/computed tomography (PET/CT) imaging and competitive binding of [18F]AlF-NOTA-NSC-GLU in human Hep3B tumor-bearing mice. The transport mechanism of [18F]AlF-NOTA-NSC-GLU was determined by competitive inhibition and protein incorporation experiments in vitro. Results: [18F]AlF-NOTA-NSC-GLU was prepared with an overall radiochemical yield of 29.3 ± 5.6% (n = 10) without decay correction within 20 min. In vitro competitive inhibition experiments demonstrated that the Na+-dependent systems X AG - , B0+, ASC, and minor X C - were involved in the uptake of [18F]AlF-NOTA-NSC-GLU, with the Na+-dependent system X AG - possibly playing a more dominant role. Protein incorporation studies of the Hep3B human hepatoma cell line showed almost no protein incorporation. Micro-PET/CT imaging with [18F]AlF-NOTA-NSC-GLU showed good tumor-to-background contrast in Hep3B human hepatoma-bearing mouse models. After [18F]AlF-NOTA-NSC-GLU injection, the tumor-to-liver uptake ratio of [18F]AlF-NOTA-NSC-GLU was 2.06 ± 0.17 at 30 min post-injection. In vivo competitive binding experiments showed that the tumor-to-liver uptake ratio decreased with the addition of inhibitors to block the XAG system. Conclusions: We have successfully synthesized [18F]AlF-NOTA-NSC-GLU as a novel PET tracer with good radiochemical yield and high radiochemical purity. Our findings indicate that [18F]AlF-NOTA-NSC-GLU may be a potential candidate for HCC imaging. Also, a further biological evaluation is underway.