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.

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.

Pharmacokinetic analysis of 6-O-[18F]FEE for PET imaging of EGFR mutation.

6-O-[18F]Fluoroethylerlotinib (6-O-[18F]FEE), with a suitable half-life for commercial distribution, may be a good replacement for [11C]erlotinib to identify epidermal growth factor receptor (EGFR) positive tumors with activating mutations to tyrosine kinase inhibitors therapy. In this study, we explored the fully automated synthesis of 6-O-[18F]FEE and investigated its pharmacokinetics in tumor-bearing mice. 6-O-[18F]FEE with high specific activity (28-100 GBq/µmol) and radiochemistry purity (over 99 %) was obtained by two-step reaction and Radio-HPLC separation in PET-MF-2 V-IT-1 automated synthesizer. PET imaging of 6-O-[18F]FEE in HCC827, A431, and U87 tumor-bearing mice with different EGFR expression and mutation was performed. Uptake and blocking of PET imaging indicated that the probe specifically targeted exon 19 deleted EGFR (the quantitative analysis of tumor-to-mouse ratio for HCC827, HCC827 blocking, U87, A431 was 2.58 ± 0.24, 1.20 ± 0.15, 1.18 ± 0.19, and 1.05 ± 0.13 respectively). Dynamic imaging was used to study the pharmacokinetics of the probe in tumor-bearing mice. Logan plot graphical analysis demonstrated late linearity and a high fitting correlation coefficient (0.998), supporting reversible kinetics. According to the Akaike Information Criterion (AIC) rule, the 2-compartment reversible model was more consistent with the metabolic properties of 6-O-[18F]FEE. The automated radiosynthesis and pharmacokinetic analysis will promote clinically transformation of 6-O-[18F]FEE.

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.

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).

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.

Automatic radiosynthesis and preclinical evaluation of 18F-AlF-PSMA-NF as a potential PET probe for prostate cancer imaging.

Facile automatic production is important for the application of prostate-specific membrane antigen (PSMA) tracers in clinical practice. We developed a new 18F-AlF-labelled PSMA probe-18F-AlF-PSMA-NF-and explore its automated production method and potential value in clinical settings. 18F-AlF-PSMA-NF was prepared using an automated method with dimethylformamide (DMF) as the solvent in a positron emission tomography (PET)-MF-2 V-IT-I synthesizer. Tracer characteristics were examined both in vitro and in vivo. Micro-PET/computed tomography (CT) was performed to investigate the utility of 18F-AlF-PSMA-NF for imaging PSMA-positive tumours in vivo. 18F-AlF-PSMA-NF was prepared automatically within 35 min with a non-attenuation correction yield of 37.9 ± 11.2%. The tracer was hydrophilic, had a high affinity for PSMA (Kd = 2.58 ± 0.81 nM), and showed stability in both in vitro and in vivo conditions. In the cellular experiments, 18F-AlF-PSMA-NF uptake in PSMA-positive LNCaP cells was significantly higher than that in PSMA-negative PC-3 cells (P < 0.001), and could be blocked by excess ZJ-43-a PSMA inhibitor (P < 0.001). LNCaP tumours were clearly visualized by 18F-AlF-PSMA-NF on micro-PET/CT, with a high level of uptake (13.72 ± 2.01 percent injected dose per gram of tissue [%ID/g]) and high tumour/muscle ratio (close to 50:1). The PSMA-positive LNCaP tumours had a significantly higher uptake than PSMA-negative PC-3 tumours (13.72 ± 2.01%ID/g vs. 1.07 ± 0.48%ID/g, t = 10.382, P < 0.001), and could be blocked by ZJ-43 (13.72 ± 2.01%ID/g vs. 2.77 ± 1.44%ID/g, t = 8.14, P < 0.001). A new 18F-AlF-labelled PSMA probe-18F-AlF-PSMA-NF-was successfully developed and can be prepared automatically. It has the biological characteristics resembling that of a PSMA-based probe and can potentially be used in clinical settings.

Radiosynthesis and biological evaluation of an fluorine-18 labeled galactose derivative [18F]FPGal for imaging the hepatic asialoglycoprotein receptor.

The asialoglycoprotein receptor (ASGPR) is abundantly expressed on the surface of hepatocytes where it recognizes and endocytoses glycoproteins with galactosyl and N-acetylgalactosamine groups. Given its hepatic distribution, the asialoglycoprotein receptor can be targeted by positron imaging agents to study liver function using PET imaging. In this study, the positron imaging agent [18F]FPGal was designed to specifically target hepatic asialoglycoprotein receptor and its effectiveness was assessed in in vitro and in vivo models. The radiosynthesis of [18F]FPGal required 50 min with total radiochemical yields of [18F]FPGal from [18F]fluoride as 10% (corrected radiochemical yield). The Kd of [18F]FPGal to ASGPR in HepG2 cells was 1.99 ± 0.05 mM. Uptake values of 0.55% were observed within 30 min of incubation with HepG2 cells, which could be blocked by 200 mM d(+)-galactose (<0.1%). In vivo biodistribution analysis showed that the liver accumulation of [18F]FPGal at 30 min was 4.47 ± 0.96% ID/g in normal mice compared to 1.33 ± 0.07% ID/g in hepatic fibrotic mice (P < 0.01). Reduced uptake in the hepatic fibrosis mouse models was confirmed through PET/CT images at 30 min. Compared to normal mice, the standard uptake value (SUV) in the hepatic fibrosis mice was significantly lower when assessed through dynamic data collection for 1 h. Therefore, [18F]FPGal is a feasible PET probe that provide insight into ASGPR related liver disease.

Radiosynthesis and preclinical evaluation of [18F]FEM as a potential novel PET probe for tumor imaging.

In the 21st century, the incidence and mortality of cancer, one of the most challenging diseases in the world, have rapidly increased. The purpose of this study was to develop 2-(2-[18F]fluoroethoxy)ethyl 4-methylbenzenesulfonate ([18F]FEM) as a positron emission tomography (PET) agent for tumor imaging. In this study, [18F]FEM was synthesized with a good radiochemical yield (45.4 ± 5.8%), high specific radioactivity (over 25 GBq/µmol), and commendable radiochemical purity (over 99%). The octanol/water partition coefficient of [18F]FEM was 1.44 ± 0.04. The probe demonstrated good stability in vitro (phosphate-buffered saline (PBS) and mouse serum (MS)), and binding specificity to five different tumor cell lines (A549, PC-3, HCC827, U87, and MDA-MB-231). PET imaging of tumor-bearing mice showed that [18F]FEM specifically accumulated at the tumor site of the five different tumor cell lines. The average tumor-to-muscle (T/M) ratio was over 2, and the maximum T/M values reached about 3.5. The biodistribution and dynamic PET imaging showed that most probes were metabolized by the liver, whereas a small part was metabolized by the kidney. Moreover, dynamic brain images and quantitative data showed [18F]FEM can quickly cross the blood brain barrier (BBB) and quickly fade out, thereby suggesting it may be a promising candidate probe for the imaging of brain tumors. The presented results demonstrated that [18F]FEM is a promising probe for tumor PET imaging.

Hierarchically Nanostructured Hybrid Platform for Tumor Delineation and Image-Guided Surgery via NIR-II Fluorescence and PET Bimodal Imaging.

Bimodal imaging with fluorescence in the second near infrared window (NIR-II) and positron emission tomography (PET) has important significance for tumor diagnosis and management because of complementary advantages. It remains challenging to develop NIR-II/PET bimodal probes with high fluorescent brightness. Herein, bioinspired nanomaterials (melanin dot, mesoporous silica nanoparticle, and supported lipid bilayer), NIR-II dye CH-4T, and PET radionuclide 64 Cu are integrated into a hybrid NIR-II/PET bimodal nanoprobe. The resultant nanoprobe exhibits attractive properties such as highly uniform tunable size, effective payload encapsulation, high stability, dispersibility, and biocompatibility. Interestingly, the incorporation of CH-4T into the nanoparticle leads to 4.27-fold fluorescence enhancement, resulting in brighter NIR-II imaging for phantoms in vitro and in situ. Benefiting from the fluorescence enhancement, NIR-II imaging with the nanoprobe is carried out to precisely delineate and resect tumors. Additionally, the nanoprobe is successfully applied in tumor PET imaging, showing the accumulation of the nanoprobe in a tumor with a clear contrast from 2 to 24 h postinjection. Overall, this hierarchically nanostructured platform is able to dramatically enhance fluorescent brightness of NIR-II dye, detect tumors with NIR-II/PET imaging, and guide intraoperative resection. The NIR-II/PET bimodal nanoprobe has high potential for sensitive preoperative tumor diagnosis and precise intraoperative image-guided surgery.

MiR-155 Enhances Insulin Sensitivity by Coordinated Regulation of Multiple Genes in Mice.

miR-155 plays critical roles in numerous physiological and pathological processes, however, its function in the regulation of blood glucose homeostasis and insulin sensitivity and underlying mechanisms remain unknown. Here, we reveal that miR-155 levels are downregulated in serum from type 2 diabetes (T2D) patients, suggesting that miR-155 might be involved in blood glucose control and diabetes. Gain-of-function and loss-of-function studies in mice demonstrate that miR-155 has no effects on the pancreatic ß-cell proliferation and function. Global transgenic overexpression of miR-155 in mice leads to hypoglycaemia, improved glucose tolerance and insulin sensitivity. Conversely, miR-155 deficiency in mice causes hyperglycemia, impaired glucose tolerance and insulin resistance. In addition, consistent with a positive regulatory role of miR-155 in glucose metabolism, miR-155 positively modulates glucose uptake in all cell types examined, while mice overexpressing miR-155 transgene show enhanced glycolysis, and insulin-stimulated AKT and IRS-1 phosphorylation in liver, adipose tissue or skeletal muscle. Furthermore, we reveal these aforementioned phenomena occur, at least partially, through miR-155-mediated repression of important negative regulators (i.e. C/EBPß, HDAC4 and SOCS1) of insulin signaling. Taken together, these findings demonstrate, for the first time, that miR-155 is a positive regulator of insulin sensitivity with potential applications for diabetes treatment.

Imaging the expression of glypican-3 in hepatocellular carcinoma by PET.

The glypican-3 (GPC3) receptor is overexpressed in hepatocellular carcinoma (HCC) and is a potential diagnostic and therapeutic target. GPC3-targeted molecular imaging will be helpful to differentiate diagnosis and guide therapy. In the present study, we will develop a novel PET probe for imaging the expression of GPC-3. L5 (sequence: RLNVGGTYFLTTRQ), a GPC3 targeting peptide, was labeled with 5-carboxyfluorescein (FAM) and 18F-fluoride. Cell binding tests were performed to identify the binding specificity of FAM-L5 and 18F radiolabeled peptide. MicroPET/CT imaging was used to determine the potential of a novel PET tracer for visualizing HCC tumors with a high expression of GPC3. In vitro binding tests showed that the uptake of FAM-L5 in HepG2 cells (high expression of GPC3) was significantly higher than that of HL-7702 cells (negative expression of GPC3) (mean fluorescent intensity: 14,094 ± 797 vs. 2765 ± 314 events, t = 32.363, P = 0.000). Confocal fluorescent imaging identified that FAM-L5 accumulated where the GPC3 receptor was located. A novel PET tracer (18F-AlF-NODA-MP-6-Aoc-L5) was successfully labeled by chelation chemistry. In vitro cell uptake studies showed that 18F-AlF-NODA-MP-6-Aoc-L5 can bind to HepG2 tumor cells and was stable in PBS and mouse serum stability tests. MicroPET/CT showed that HepG2 tumors could be clearly visualized with a tumor/muscle ratio of 2.46 ± 0.53. However, the tumor/liver ratio was low (0.93 ± 0.16) due to the high physiological uptake in the liver. This study demonstrates that FAM and the 18F-labeled L5 peptide can selectively target HCC with a high expression of GPC3 in vitro and in vivo. 18F-AlF-NODA-MP-C6-L5 has the potential to be a GPC3 target tracer but requires some chemical modifications to achieve a high enough tumor/liver ratio for detection of the tumor in the liver.

Radiosynthesis and biological evaluation of 18F-labeled 4-anilinoquinazoline derivative (18F-FEA-Erlotinib) as a potential EGFR PET agent.

Epidermal growth factor receptor (EGFR) has gained significant attention as a therapeutic target. Several EGFR targeting drugs (Gefitinib and Erlotinib) have been approved by US Food and Drug Administration (FDA) and have received high approval in clinical treatment. Nevertheless, the curative effect of these medicines varied in many solid tumors because of the different levels of expression and mutations of EGFR. Therefore, several PET radiotracers have been developed for the selective treatment of responsive patients who undergo PET/CT imaging for tyrosine kinase inhibitor (TKI) therapy. In this study, a novel fluorine-18 labeled 4-anilinoquinazoline based PET tracer, 1N-(3-(1-(2-18F-fluoroethyl)-1H-1,2,3-triazol-4-yl)phenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (18F-FEA-Erlotinib), was synthesized and biological evaluation was performed in vitro and in vivo. 18F-FEA-Erlotinib was achieved within 50min with over 88% radiochemical yield (decay corrected RCY), an average specific activity over 50GBq/µmol, and over 99% radiochemical purity. In vitro stability study showed no decomposition of 18F-FEA-Erlotinib after incubated in PBS and FBS for 2h. Cellular uptake and efflux experiment results indicated the specific binding of 18F-FEA-Erlotinib to HCC827 cell line with EGFR exon 19 deletions. In vivo, Biodistribution studies revealed that 18F-FEA-Erlotinib exhibited rapid blood clearance both through hepatobiliary and renal excretion. The tumor uptake of 18F-FEA-Erlotinib in HepG2, HCC827, and A431 tumor xenografts, with different EGFR expression and mutations, was visualized in PET images. Our results demonstrate the feasibility of using 18F-FEA-Erlotinib as a PET tracer for screening EGFR TKIs sensitive patients.

Anti-inflammatory Effect of Mesenchymal Stromal Cell Transplantation and Quercetin Treatment in a Rat Model of Experimental Cerebral Ischemia.

Here, we have investigated the synergistic effect of quercetin administration and transplantation of human umbilical cord mesenchymal stromal cells (HUMSCs) following middle cerebral artery occlusion in rat. Combining quercetin treatment with delayed transplantation of HUMSCs after local cerebral ischemia significantly (i) improved neurological functional recovery; (ii) reduced proinflammatory cytokines (interleukin(IL)-1ß and IL-6), increased anti-inflammatory cytokines (IL-4, IL-10, and transforming growth factor-ß1), and reduced ED-1 positive areas; (iii) inhibited cell apoptosis (caspase-3 expression); and (iv) improved the survival rate of HUMSCs in the injury site. Altogether, our results demonstrate that combined HUMSC transplantation and quercetin treatment is a potential strategy for reducing secondary damage and promoting functional recovery following cerebral ischemia.

Optimal clinical protocols for total-body 18F-FDG PET/CT examination under different activity administration plans.

BACKGROUND: Highly sensitive digital total-body PET/CT scanners (uEXPLORER) have great potential for clinical applications and fundamental research. Given their increasing sensitivity, low-dose scanning or snapshot imaging is now possible in clinics. However, a standardized total-body 18F-FDG PET/CT protocol is still lacking. Establishing a standard clinical protocol for total-body 18F-FDG PET/CT examination under different activity administration plans can help provide a theoretical reference for nuclear radiologists. METHODS: The NEMA image quality (IQ) phantom was used to evaluate the biases of various total-body 18F-FDG PET/CT protocols related to the administered activity, scan duration, and iterations. Several objective metrics, including contrast recovery (CR), background variability (BV), and contrast-to-noise ratio (CNR), were measured from different protocols. In line with the European Association of Nuclear Medicine Research Ltd. (EARL) guidelines, optimized protocols were suggested and evaluated for total-body 18F-FDG PET/CT imaging for three different injected activities. RESULTS: Our NEMA IQ phantom evaluation resulted in total-body PET/CT images with excellent contrast and low noise, suggesting great potential for reducing administered activity or shortening the scan duration. Different to the iteration number, prolonging the scan duration was the first choice for achieving higher image quality regardless of the activity administered. In light of image quality, tolerance of oncological patients, and the risk of ionizing radiation damage, the 3-min acquisition and 2-iteration (CNR = 7.54), 10-min acquisition and 3-iteration (CNR = 7.01), and 10-min acquisition and 2-iteration (CNR = 5.49) protocols were recommended for full-dose (3.70 MBq/kg), half-dose (1.95 MBq/kg), and quarter-dose (0.98 MBq/kg) activity injection schemes, respectively. Those protocols were applied in clinical practices, and no significant differences were observed for the SUVmax of large/small lesions or the SUVmean of different healthy organs/tissues. CONCLUSION: These findings support that digital total-body PET/CT scanners can generate PET images with a high CNR and low-noise background, even with a short acquisition time and low administered activity. The proposed protocols for different administered activities were determined to be valid for clinical examination and can maximize the value of this imaging type.

In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [11C]OCM-44 and [18F]OCM-50 in Non-Human Primates.

Glycogen synthase kinase 3 (GSK-3) is a potential therapeutic target for a range of neurodegenerative and psychiatric disorders. The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [11C]OCM-44 and [18F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03-0.25 mg/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [11C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [11C]OCM-44 volume of distribution (VT) values in the brain increased with time; VT values from models fitted to truncated 60-min scan data were 1.4-2.9 mL/cm3 across brain regions. The plasma free fraction was 0.6% for [18F]OCM-50 and VT values (120-min) were 0.39-0.87 mL/cm3 in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional VT indicated >80% target occupancy by 0.1 mg/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [11C]OCM-44 and [18F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis.

A proper protocol for routine 18F-FDG uEXPLORER total-body PET/CT scans.

BACKGROUND: Conventional clinical PET scanners typically have an axial field of view (AFOV) of 15-30 cm, resulting in limited coverage and relatively low photon detection efficiency. Taking advantage of the development of long-axial PET/CT, the uEXPLORER PET/CT scanner with an axial coverage of 194 cm increases the effective count rate by approximately 40 times compared to that of conventional PET scanners. Ordered subset expectation maximization (OSEM) is the most widely used iterative algorithm in PET. The major drawback of OSEM is that the iteration process must be stopped before convergence to avoid image degradation due to excessive noise. A new Bayesian penalized-likelihood iterative PET reconstruction, named HYPER iterative, was developed and is now available on the uEXPLORER total-body PET/CT, which incorporates a noise control component by using a penalty function in each iteration and finds the maximum likelihood solution through repeated iterations. To date, its impact on lesion visibility in patients with a full injected dose or half injected dose is unclear. The goal of this study was to determine a proper protocol for routine 18F-FDG uEXPLORER total-body PET/CT scans. RESULTS: The uEXPLORER total-body PET/CT images reconstructed using both OSEM and HYPER iterative algorithms of 20 tumour patients were retrospectively reviewed. The quality of the 5 min PET image was excellent (score 5) for all of the dose and reconstruction methods. Using the HYPER iterative method, the PET images reached excellent quality at 1 min with full-dose PET and at 2 min with half-dose PET. The PET image reached a similar excellent quality at 2 min with a full dose and at 3 min with a half dose using OSEM. The noise in the OSEM reconstruction was higher than that in the HYPER iterative. Compared to OSEM, the HYPER iterative had a slightly higher SUVmax and TBR of the lesions for large positive lesions (≥ 2 cm) (SUVmax: up to 9.03% higher in full dose and up to 12.52% higher in half dose; TBR: up to 8.69% higher in full dose and up to 23.39% higher in half dose). For small positive lesions (≤ 10 mm), the HYPER iterative had an obviously higher SUVmax and TBR of the lesions (SUVmax: up to 45.21% higher in full dose and up to 74.96% higher in half dose; TBR: up to 44.91% higher in full dose and up to 93.73% higher in half dose). CONCLUSIONS: A 1 min scan with a full dose and a 2 min scan with a half dose are optimal for clinical diagnosis using the HYPER iterative and 2 min and 3 min for OSEM. For quantification of the small lesions, HYPER iterative reconstruction is preferred.

Superiority of 11 C-Choline PET/CT in the Delineation of a Rare Intracranial Diffuse Embryonic Tumor.

ABSTRACT: Intracranial diffuse embryonal tumor in the adult is rare. We report a young woman with a diffuse embryonal malignancy in the saddle area, which was depicted well by 11 C-choline PET/CT, superior to 18 F-FDG PET/CT and contrast-enhanced MRI. Under the guiding of 11 C-choline PET/CT, the biopsy was successfully performed and the diagnosis was established. This case highlights that 11 C-chione PET/CT may be useful to diagnose and delineate the intracranial diffuse embryonic tumors.