ABSTRACT
Abstract Prostate-specific membrane antigen (PSMA) is a transmembrane protein expressed in normal prostate cells and overexpressed in prostate cancer. Consequently, it is an important tool in the evaluation of prostate cancer, including the staging of high-risk patients and the assessment of biochemical recurrence. Despite the "specific" designation, benign musculoskeletal conditions, such as fractures, osteodegenerative changes, and fibrous dysplasia, can also show PSMA uptake, which can lead to misinterpretation of the imaging findings. Therefore, radiologists must be aware of these potential pitfalls, understand their causes, and fully analyze their morphologic features on unfused computed tomography (CT) and magnetic resonance imaging scans to correctly interpret the examination. In this pictorial essay, we review the basic characteristics of the 68Ga-PSMA positron-emission tomography/CT (PET/CT) radiotracer, discuss potential causes of false-positive findings on 68Ga-PSMA PET/CT in the musculoskeletal system, and illustrate the corresponding imaging findings.
Resumo O antígeno de membrana próstata específico (PSMA) é uma proteína transmembrana que apresenta expressão em células prostáticas normais e superexpressão em neoplasia da próstata. Dessa forma, é uma importante ferramenta na avaliação da neoplasia prostática, de utilidade no estadiamento de pacientes de alto risco e na análise de recorrência bioquímica. Apesar do termo "específico", condições musculoesqueléticas benignas podem demonstrar captação de PSMA, como fraturas, alterações osteodegenerativas e displasia fibrosa, podendo levar a uma avaliação equivocada dos achados de imagem. Assim, o radiologista deve conhecer esses potenciais pitfalls, compreender suas causas e analisar as características morfológicas nas imagens não fundidas de TC e RM para interpretar corretamente o exame. Neste ensaio iconográfico, revisaremos as características básicas do radiofármaco 68Ga-PSMA PET/CT, discutiremos possíveis causas de resultados falso-positivos na 68Ga-PSMA PET/CT no sistema musculoesquelético e ilustraremos os achados de imagem correspondentes.
ABSTRACT
Objective:To produce 68Ga and automatically synthesize 68Ga-labeled drugs based on low-energy medical cyclotron solid target system. Methods:68Zn was electroplated on the surface of the target by electrodeposition. According to the principle of 68Zn(p, n) 68Ga nuclear reaction, 68Zn was irradiated by the 10 MeV medical cyclotron solid target system (30 μA, 30 min) to produce 68Ga, and the activity, nuclear purity, half-life and content of metal impurities of purified product were determined. 68Ga-prostate specific membrane antigen (PSMA)-11 and 68Ga-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid- D-Phe1-Tyr3-Thr8-octreotide (DOTATATE) were synthesized automatically using 68Ga respectively, and the quality control analyses of drug properties, concentration, pH, radiochemical purity, sterility and bacterial endotoxin were carried out. Results:The electroplating mass of 68Zn was (43.71±0.87) mg ( n=35), the yield of 68Ga after irradiation was (10.96±0.67) GBq ( n=35), and the measured half-life was (67.64±0.06) min ( n=7). Only 511 keV energy peak was detected by the gamma spectrometer. After purification, (6.85±0.12) GBq ( n=35) of pure 68Ga was obtained, and the purification efficiency was (62.46±0.96)% (non-attenuated correction, n=35). The metal impurity contents of Zn and Fe were (0.18±0.06) and (1.25±0.43) μg/GBq ( n=5), which met the requirements of European Pharmacopoeia. Three batches of 68Ga-PSMA-11 and 68Ga-DOTATATE were automatically synthesized, with the yield, concentration and radiochemical purity of (3.54±0.14) and (2.74±0.20) GBq, (294.97±11.58) and (228.17±16.32) GBq/L, (99.73±0.11)% and (99.45±0.25)%, respectively. Both sterility and bacterial endotoxin were qualified. Conclusion:High-yield and qualified nuclide 68Ga and 68Ga-labeled drugs are successfully prepared through the low-energy medical cyclotron solid target system and the automated purification and synthesis module, which provide a strong guarantee for clinical practice.
ABSTRACT
Objective:To investigate the clinical application of 68Ga-cyclo( L-arginylglycyl- L-α-aspartyl- D-tyrosyl-N6-(((4, 7-bis(carboxymethyl)-1, 4, 7-triazonan-1-yl)acetyl))- L-lysyl) (NODAGA-RGD) PET/CT to evaluate short-term efficacy of tyrosine kinase inhibitor (TKI) in distant metastatic differentiated thyroid cancer (dmDTC). Methods:From October 2019 to March 2023, 13 dmDTC patients (5 males, 8 females; age: 68(65, 69) years) from Nanjing First Hospital were retrospectively enrolled, of which 9 were clinically confirmed as radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and 4 were dmDTC without radioactive iodine treatment. All patients underwent 68Ga-NODAGA-RGD PET/CT to assess neovascularization of the target lesions (TL), and the SUV max and target background ratio (T/B) were recorded. After 3 months of TKI treatment (anrotinib ( n=9) or apatinib ( n=4)), change rates of the maximum diameter of TL and thyroglobulin (Tg) were measured. The correlation of SUV max, T/B and the change rate of the maximum diameter of TL were analyzed by Spearman rank correlation analysis. ROC curve analysis was performed for the effectiveness of the T/B and TKI therapy, and the difference of the remission rate of lesions was analyzed by Fisher exact test. Results:In 13 patients, 36 TL were measured by 68Ga-NODAGA-RGD PET/CT with SUV max of 5.44(3.43, 7.56) and T/B of 5.25(4.50, 7.23). The change rate of the maximum diameter of TL was -30%(-39%, -21%) and the change rate of Tg was -68%(-96%, -52%). T/B was negatively correlated with the change rate of the maximum diameter of TL after TKI therapy ( rs=-0.46, P=0.005), while SUV max was not correlated with the change rate of the maximum diameter of TL ( rs=0.03, P=0.883). ROC curve analysis showed that the optimal cut-off value for T/B was 4.95, with the AUC of 0.698, the sensitivity of 87.5%, and the specificity of 60.0%. Compared to lesions with T/B<4.95, those with T/B≥4.95 showed higher remission rate (2/14 vs 63.6%(14/22); P=0.006). After 3 months of TKI treatment, the disease control rate was 12/13. Conclusion:68Ga-NODAGA-RGD PET/CT can effectively reflect tumor neovascularization, predict efficacy of TKI therapy, and provide powerful imaging evidence for TKI therapy in dmDTC.
ABSTRACT
Objective:To develop a tetramer probe targeting fibroblast activation protein (FAP), named 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-4P(FAP inhibitor (FAPI)) 4, evaluate its biodistribution and PET image in FAP-positive-tumor bearing nude mice, and explore its feasibility as a novel radio-regent for treatment of FAP-positive tumor. Methods:FAP tetramer probe was constructed on the FAPI-46 motif with four mini-polyethylene glycol (PEG)(PEG 3) spacers between the four FAPI motifs, denoted as 4P(FAPI) 4. DOTA was used as the chelator for radiolabeling with 68Ga and 177Lu. The FAP binding characteristics were test by in vitro cell competitive binding experiment. Small-animal PET, in vivo biodistribution, and radionuclide targeting therapy were performed in HT-1080-FAP tumor bearing nude mice ( n=39). Independent-sample t test was performed to analyze tumor uptake data, and two-factor repeated measures analysis of variance was utilized to compare tumor volume data in radioactive isotope therapy. Results:Cell experiment showed that FAPI-tetramer and FAPI-monomer had similar half maximal inhibitory concentration values (3.29 and 2.15 nmol/L). 68Ga/ 177Lu radiolabeled FAPI-tetramer had better tumor uptake and retention than FAPI-monomer in small-animal PET and in vivo biodistribution experiment, with the tumor uptake for 177Lu-DOTA-4P(FAPI) 4 and 177Lu-FAPI-46 at 48 h of (18.72±1.32) vs (2.72±1.20) percentage activity of injection dose per gram of tissue (%ID/g) ( t=15.55, P<0.001). 177Lu-DOTA-4P(FAPI) 4 group showed best anti-tumor efficacy compared with 177Lu-FAPI-46 and control group in radionuclide targeting therapy. On the 2nd day after the start of treatment, the tumor volume in the tetramer treatment group was significantly smaller than that in the control group (mean difference 67.19 mm 3, P=0.049); on the 14th day after the start of treatment, the tumor volume in the tetramer treatment group was significantly smaller than that in the monomer treatment group (mean difference 414.33 mm 3, P=0.005). Conclusion:FAPI-tetramer can improve tumor uptake and retention ability compared with FAPI-46, and 177Lu-DOTA-4P(FAPI) 4 can be a promising radio-agent for FAP-positive tumor therapy.
ABSTRACT
Objective:To investigate the diagnostic and prognostic value of 68Ga-fibroblast activation protein inhibitor (FAPI) PET for hepatobiliary malignancies. Methods:From July 2020 to February 2023, 33 patients (23 males, 10 females; age (55.4±13.5) years) with suspected or confirmed liver or biliary tract malignancies who underwent 68Ga-FAPI PET in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology were retrospectively analyzed. PET images were evaluated by 3 experienced nuclear medicine physicians, and the results of biopsy or postoperative pathology, clinical and imaging follow-up were used as the gold standard. One-way analysis of variance and least significant difference t test were used to compare the differences among groups. Survival analysis was performed using Kaplan-Meier curves and the log-rank test. Results:Of 33 patients, 14 performed PET for initial diagnosis and staging, and 19 for restaging. There were 14 patients with hepatocellular carcinoma (HCC), 13 patients with cholangiocarcinoma (CCA), and 6 patients with gallbladder carcinoma (GBC). The primary tumor of HCC, CCA and GBC all showed significant 68Ga-FAPI uptake, with no statistically significant difference in SUV max among groups ( F=1.58, P=0.250). The sensitivities of 68Ga-FAPI PET for initial diagnosis and restaging of hepatobiliary malignancies were 14/14 and 15/15, respectively. Compared with conventional imaging, 68Ga-FAPI PET changed the diagnosis and staging in 29.2%(7/24) patients. The treatment strategy was changed in 30.3%(10/33) patients with malignant tumors due to 68Ga-FAPI PET findings. Follow-up showed 22 cases survived and 11 cases died, with the overall survival of 355.56(80.00, 516.97) d, and 1- and 2-year survival rates were 68.2% and 57.9%, respectively. Semi-quantitative 68Ga-FAPI PET parameters such as SUV max, target-liver ratio (TLR), and target-blood ratio (TBR) had no significant prognostic value, but the prognosis of the group without distant metastases diagnosed by 68Ga-FAPI PET was significantly better than that of the group with distant metastasis ( P=0.032). Conclusion:68Ga-FAPI PET has high sensitivity for the diagnosis of hepatobiliary malignancies, which can help guide treatment decisions and prognosis evaluation.
ABSTRACT
Objective:To explore the value of 68Ga-prostate specific membrane antigen (PSMA)-11 PET/CT in newly diagnosed prostate cancer patients with different risk stratifications, and to compare the performance of this modality with conventional imaging in detecting metastases. Methods:From June 2019 to July 2020, the clinical and imaging data of 60 patients (age range: 44-88 years, median age 69 years) who underwent 68Ga-PSMA-11 PET/CT imaging in Fudan University Shanghai Cancer Center were retrospectively analyzed. Spearman rank correlation analysis was used to explore the correlation of SUV max in primary foci with prostate specific antigen (PSA) and Gleason score (GS). Based on the D′Amico risk stratification (PSA>20 μg/L and ≤20 μg/L, GS>7 and ≤7), the detection rates of 68Ga-PSMA-11 PET/CT for metastases were evaluated by χ2 test, and the differences of SUV max were analyzed by Mann-Whitney U test. Patients were divided into high-risk (PSA>20 μg/L and GS>7), medium-risk (PSA>20 μg/L and GS≤7, or PSA≤20 μg/L and GS>7), and low-risk (PSA<20 μg/L and GS<7) groups according to PSA levels and GS. Compared with conventional imaging (bone imaging, CT or MRI), the ability of 68Ga-PSMA-11 PET/CT to detect metastatic tumors, and the utility to change the prostate cancer stage were evaluated by Fisher′s exact test. Results:High uptake of 68Ga-PSMA-11 was observed in primary lesions of 60 patients, and SUV max was positively correlated with GS or PSA ( rs values: 0.42, 0.38; P values: 0.001, 0.002). The detection rates of lymph node and bone metastases in the group with PSA>20 μg/L were 11/18 and 13/18, respectively, which were higher than those in the group with PSA≤20 μg/L (28.57%(12/42) and 35.71%(15/42); χ2 values: 6.56, 7.56, P values: 0.010, 0.006. However, there was no statistical significance in the SUV max of these lesions( z values: -1.04, -0.96; P values: 0.299, 0.337). There was a statistical difference in the detection rates of lymph node and bone metastases between the group with GS>7 and the group with GS≤7 (lymph node: 54.05%(20/37) vs 13.04%(3/23), χ2=10.09, P=0.001; bone metastases: 59.46%(22/37) vs 26.09%(6/23), χ2=8.19, P=0.004), as well as the SUV max of bone metastases( z=-2.02, P=0.044). In the high-risk group, 68Ga-PSMA-11 PET/CT had the higher detection rate of metastases than conventional imaging (16/17 vs 10/17; P=0.039) and it changed 25.0%(15/60) of the patients′ staging. Conclusions:PSA and GS affect the detection rate of 68Ga-PSMA-11 PET/CT. In patients with high-risk prostate cancer, 68Ga-PSMA-11 PET/CT is superior to conventional imaging in detecting metastases. When PSA>20 μg/L and GS>7, it is better to use 68Ga-PSMA-11 PET/CT in prostate cancer staging.
ABSTRACT
Objective:To explore the relation of the radiochemical purity and in vivo imaging effect of 68Ga-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)- D-phe1-Tyr3-Thr8-octreotide (TATE) injection. Methods:High performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) methods were established to determine 68Ga-DOTATATE, 68Ga 3+ , 68Ga in colloidal form and 68Ga-DOTA- D-Phe1-Tyr3-Thr8-dethreonine-octreotide (heptapeptide) and to study the influence of precursor purity on radiochemical purity of labelled products. The uptake of 68Ga-DOTATATE injection with different radiochemical purities was investigated in nude mice bearing AR42J cells by microPET imaging and the tumor target/non-target (T/NT) value was calculated. One-way analysis of variance and Pearson correlation analysis were used to analyze the data. Results:The contents of 68Ga 3+ and 68Ga in colloidal form were not related with precursor purity ( r values: 0.385, 0.497, P values: 0.306, 0.137), while the content of 68Ga-DOTA-heptapeptide was positively related with the purity of DOTA-heptapeptide ( r=0.957, P<0.001). The radiochemical purities of 68Ga-DOTATATE injection were (87.0±2.3)%, (86.8±0.8)% and (94.0±3.1)% when the DOTATATE purities were 90.9%, 91.6% and 99.2%, respectively. The results of microPET imaging showed that the tumor uptake was positively related with the radiochemical purity of 68Ga-DOTATATE injection ( r=0.828, P<0.001), and the T/NT values of 68Ga-DOTATATE injection with radiochemical purities of 95.7%, 85.8%, 84.5% and 79.9% were 21.25±8.84, 8.50±1.51, 11.38±1.65 and 6.01±0.99, respectively ( F=11.48, P=0.001). Conclusion:The radiochemical purity of 68Ga-DOTATATE injection is impacted by the purity of labelled precursor and manufacturing processes and is related with the imaging effect in vivo.
ABSTRACT
Objective:To explore the value of SPECT/CT imaging on programmed death receptor 1 ligand (PD-L1) expression in patients with non-small cell lung cancer (NSCLC) based on 99Tc m labeled anti-PD-L1 nanoantibodies (NM-01). Methods:From January 2019 to March 2020, a total of 14 patients (11 males, 3 females; age: (61.9±11.0) years) with pathologically confirmed NSCLC in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine were prospectively enrolled. NM-01 were labeled with 99Tc m, and patients were recruited for SPECT/CT imaging 2 h after injection with 99Tc m-NM-01((359.1±68.0) MBq). The differences of SUV max in primary and metastatic lesions between PD-L1 positive and negative patients were compared by independent sample t test. The correlation between the SUV max and PD-L1 expression of primary lesions was analyzed by Pearson correlation analysis. Results:Of 14 patients, 6 were PD-L1 positive and 8 were PD-L1 negative. 99Tc m-NM-01 showed obviously increased uptake in kidneys and liver, while mildly increased uptake in spleen and bone marrow. The SUV max of primary lesions was 4.69±1.88 and the SUV max of metastatic lesions was 2.04±1.32. The SUV max of primary lesions in PD-L1 positive patients was significantly higher than that of PD-L1 negative patients (5.99±1.99 vs 3.72±1.10; t=5.98, P=0.039). There was no significant difference in the SUV max of metastatic lesions between PD-L1 positive and negative patients (1.66±1.03 vs 2.35±1.46; t=-1.77, P=0.084). The SUV max of primary lesions was positively correlated with PD-L1 expression ( r=0.648, P=0.042). Conclusion:99Tc m-NM-01 can demonstrate the expression of PD-L1 in primary and metastatic lesions in NSCLC.
ABSTRACT
Objective:To explore the feasibility of pretargeting technique for immunoPET with epidermal growth factor receptor (EGFR) monoclonal antibody in EGFR positive/negative tumor bearing mice.Methods:Cetuximab- Trans-cyclooctene (TCO)was obtained by modifying Cetuximab with TCO- N-hydroxysuccinimide (NHS). 2, 2′-((6-amino-1-(4, 7-bis-(carboxymethyl)-1, 4, 7-triazonan-1-yl)hexan-2-yl)azanediyl)-diacetic acid (L-NETA)was used as a chelating agent to prepare the radioligand 68Ga-L-NETA-tetrazine (Tz), then the labeling rate and in vitro stability of the product were determined. Human basal breast cancer cells MDA-MB-468 (EGFR+ ) and MDA-MB-231 (EGFR-) were cultured in vitro. In vitro experiments were performed to explore the specificity of the probe and the feasibility of pretargeting technique. Nude mice (Balb/c-nu) bearing xenografts of the above two cell lines were established. Cetuximab-TCO (50 μg) was injected into the tumor-bearing mice in advance, then 68Ga-L-NETA-Tz was injected at different time points (48, 36, 24 and 12 h), and pretargeting was realized through " click chemistry" . Small-animal PET imaging and biodistribution were performed to evaluate pharmacokinetic properties and specificity of the probe. The one-way analysis of variance was used to compare the data. Results:The 68Ga-L-NETA-Tz molecular probe was successfully prepared with the labeling yield >95%, and the radiochemical purity was >95% after 2 h. Cetuximab-TCO and 68Ga-L-NETA-Tz were added to MDA-MB-468 cells successively, and the cell uptake rate reached (0.69±0.04)% at 1 h, which demonstrated the feasibility of the pretargeting technique. PET imaging and biodistribution results showed that the best imaging results were obtained in 36 h pre-injection group, in which the tumor uptake was the highest ((0.77±0.05) percentage activity of injection dose per gram of tissue (%ID/g), 1 h) and the tumor/muscle ratio was optimal (4.67±0.46); the tumor uptake in the blocking group, the group without injecting Cetuximab-TCO, and the MDA-MB-231 group were significantly lower ((0.35±0.01), (0.39±0.05), (0.45±0.10) %ID/g; F=15.50, P=0.002). Conclusions:EGFR targeted immunoPET imaging is successfully performed in mouse models of breast cancer by injecting Cetuximab-TCO and 68Ga-L-NETA-Tz successively. It provides an effective method for immunoPET imaging of monoclonal antibodies.
ABSTRACT
Objective:To synthesize a novel site-specifically labelled probe 68Ga-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-Cys-Asp-Val (CDV)-Nb109 and explore its potential for detection of the programmed cell death ligand 1 (PD-L1) expression level in different tumors. Methods:Firstly, CDV was inserted into the tail of the sequence of Nb109 by genetic engineering. Then the precursor DOTA-CDV-Nb109 was prepared by mixing the maleimide-DOTA and the single-domain antibody CDV-Nb109 (amount of substance ratio 1∶1) via the maleimide-cysteine site-specific coupling strategy. Subsequently, the DOTA-CDV-Nb109 was labeled with 68Ga and purified by PD-10 column. Human melanoma A375, human PD-L1 transfected melanoma A375-hPD-L1 and human glioma U87 tumor-bearing mice models were established, and the diagnostic value of 68Ga-DOTA-CDV-Nb109 was evaluated by stability assay, cellular uptake, and microPET imaging. One-way analysis of variance and the least significant difference t test were used to analyze the data. Results:The probe 68Ga-DOTA-CDV-Nb109 was obtained with the radiochemical yield of (69.79±4.69)%, radiochemical purity more than 97%, and molar activity of (12.85±1.51) GBq/μmol. 68Ga-DOTA-CDV-Nb109 had strong binding affinity for A375-hPD-L1 with the dissociation constant ( Kd) of (66.43±17.89) nmol/L. The uptake of 68Ga-DOTA-CDV-Nb109 in A375-hPD-L1 and U87 cells were (3.17±0.15) percentage of the added radioactivity dose (%AD) and (2.08±0.03) %AD respectively, which were significantly higher than that in A375 cells ((1.21±0.14) %AD; F=82.87, t values: 15.23, 9.98, P values: <0.001, 0.003). The tumor uptake of the probe in A375-hPD-L1 ((5.21±0.35) percentage of injected dose per ml (%ID/ml)) and U87 tumor-bearing mice ((3.44±0.69) %ID/ml) were significantly higher than that in A375 tumor-bearing mice ((2.17±0.36) %ID/ml; F=249.72, t values: 35.70, 3.43, both P<0.001). Conclusion:The site-specifically labelled probe 68Ga-DOTA-CDV-Nb109, which can non-invasively and dynamically monitor the change of PD-L1 expression level in different tumors and help screen patients who can benefit from PD-L1 immune checkpoint blocking therapy, is successfully synthesized with high radiochemical purity.
ABSTRACT
Objective:To investigate the kinetic metrics of 68Ga-fibroblast activation protein inhibitor (FAPI)-04 in pancreatic cancers and normal organs by using total-body PET dynamic imaging. Methods:From December 2020 to December 2021, 68Ga-FAPI-04 total-body PET/CT dynamic imaging were performed on 6 pancreatic cancer patients (3 males, 3 females, median age 55.5 years) in Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. Images were respectively analyzed. Manual delineations of volume of interests (VOIs) on multiple normal organs and pathological lesions were performed and time-to-activity curves (TACs) were generated. A reversible two-tissue compartment model (2TCM) was fitted for each tissue TAC. Rate constants including K1, k2, k3 and k4, and the total volume of distribution ( Vt) were obtained and compared by tissue types. Wilcoxon rank sum test and Spearman correlation analysis were used for data analysis. Results:Kinetic metrics varied significantly among normal organs and pancreatic cancer lesions ( z values: 2.00-1 240.00, all P<0.05). The highest K1 among lesions was observed in primary tumor (0.30 min -1), which was observed in the spleen (1.42 min -1) among normal organs. The highest k2 among lesions was observed in peritoneal metastases (0.24 min -1), which was observed in the spleen (2.59 min -1) among normal organs. Primary tumor showed the highest k3 of 0.17 min -1 among lesions, and the pancreas had the highest k3 of 0.16 min -1 among normal organs. Primary tumor had the highest k4 of 0.03 min -1 among lesions, and the heart, lungs, parotid glands had high k4(0.06 min -1) among normal organs. Vt were higher in pathological lesions compared to normal organs, with the highest in primary tumor (13.78 ml/cm 3). There were correlations between Vt in lesions and SUV mean( rs=0.86, P<0.001) or SUV max ( rs=0.77, P<0.001). Conclusion:The rate constants including K1, k2, k3 and k4, and Vt of 68Ga-FAPI-04 vary among normal organs and lesions.
ABSTRACT
Objective:To evaluate the specificity of 68Ga-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-Ser-Asn-Thr-Arg-Val-Ala-Pro (SNTRVAP, VAP) molecular probe targeting glucose-regulated protein 78(GRP78) in vivo and in vitro and the feasibility of 68Ga-DOTA-VAP microPET/CT imaging in the diagnosis of GRP78-positive tumors. Methods:68Ga-DOTA-VAP was prepared by the combination of bifunctional chelating agent DOTA and VAP, followed by 68Ga labeling. Western blotting experiment was perfomed to detect the expression of GRP78 in U87MG, BxPC-3, and 293T cell lines, at the same time, cold polypeptide blocked experiments were conducted to verify the specific binding of 68Ga-DOTA-VAP to cells. U87MG and BxPC-3 subcutaneous transplantation tumor mouse models were established and the biodistribution of 68Ga-DOTA-VAP were explored in vivo. The imaging effect of 68Ga-DOTA-VAP in GRP78-positive tumor-bearing mouse models was evaluated by microPET/CT. Independent-sample t test, one-way analysis of variance and Dunnett t test were used for data analysis. Results:68Ga-DOTA-VAP was easily prepared with labeling yield and radiochemical purity >98%. It had good stability in vitro, and its radiochemical purity was still (98.27±0.22)% after 2 h. GRP78 was highly expressed in U87MG and BxPC-3 cells, but lowly expressed in 293T cells ((0.78±0.02), (0.53±0.05) and (0.36±0.03), F=102.22, P<0.001; t values: 0.43, 0.18, both P<0.01). The uptake of 68Ga-DOTA-VAP in U87MG cells was higher than that in BxPC-3 cells (5 154.00±216.70 vs 4 344.00±60.88; t=3.10, P=0.027). Excessive unlabeled VAP polypeptide could significantly reduce the uptake of 68Ga-DOTA-VAP both in U87MG and BxPC-3 cells (3 324.00±54.14, 3 270.00±131.10; t values: 8.19, 7.43, both P<0.01). The uptake of 68Ga-DOTA-VAP in U87MG tumor tissue was higher than that in BxPC-3 tumor tissue ((1.98±0.20) vs (1.30±0.08) percentage activity of injection dose per gram of tissue (%ID/g); t=5.48, P=0.005), while co-injection of excessive unlabeled VAP polypeptide significantly reduced the uptake in U87MG and BxPC-3 tumors ((0.99±0.02) and (0.62±0.05) %ID/g; t values: 8.32, 12.25, both P<0.05). MicroPET/CT imaging showed that 68Ga-DOTA-VAP could clearly display U87MG and BxPC-3 tumors, and U87MG had a better imaging effect. The tumors could not be clearly visualized after co-injection of excessive VAP polypeptide. Conclusion:68Ga-DOTA-VAP molecular probe binds with GRP78 specifically and can reflect the expression level of GRP78 in vivo, which may be a promising probe for the specific imaging diagnosis of GRP78-positive tumors.
ABSTRACT
Objective:To compare the effect of different β values on the semi-quantitative accuracy and image quality of 68Ga-prostate specific membrane antigen (PSMA) PET/CT imaging after partial volume effect correction (PVC). Methods:In the model experiment, image reconstruction was carried out based on block sequential regularized expectation maximization algorithm (BSREMA) with the range of β values from 100 to 1 000. Recovery coefficient (RC), contrast recovery (CR) and background variability (BV) were measured to evaluate semi-quantitative accuracy and image quality. In the clinical study, image data of 21 prostate cancer patients (age 45-78 years) who underwent 68Ga-PSMA PET/CT examination in the First Hospital of Shanxi Medical University from March 2019 to February 2020 were retrospectively collected. A total of 29 abdominal imaging positive lymph nodes were divided into the small lymph node group (diameter <10 mm; n=12) and the large lymph node group (10 mm≤diameter≤30 mm; n=17). SUV parameters including SUV max, SUV mean and peak of SUV (SUV peak) and the influence of different β values on the SUV parameters were evaluated. The signal to noise ratio (SNR) and subjective scores were used to evaluate image quality. Independent-sample t test, Kappa test and Pearson correlation analysis were used to analyze data. Results:The model experiment showed that CR, RC and BV decreased with the increase of β values. The image quality, image clarity, lesion significance, and total image scores given by nuclear medicine physicians showed strong consistency ( Kappa values: 0.65-0.87, P values: 0.026-0.043). The small lymph node group had the highest score (13 and 14) with β value of 600, while the large lymph node group had the highest score (13 and 14) with β value of 700. SNR of the two groups increased steadily within β values from 100 to 600 ( t values: 2.49-8.99, P values: 0.023-0.038). When the β value was higher than 600, SNR of the small lymph node group reached a plateau ( t values: 1.28-2.00, P values: 0.072-0.098), while the SNR of the large lymph node group continued to increase ( t values: 2.98-4.63, P values: 0.012-0.029). Before PVC, there were significant negative correlations between SUV parameters and β values ( r values: from -0.94 to -0.64, P values: 0.039-0.046). After PVC, it was found that SUV mean and SUV max still had significant negative correlation with β values ( r values: from -0.78 to -0.68, P values: 0.035-0.042), while the SUV peak showed no significant correlation with β values ( r values: -0.22, -0.28, P values: 0.069, 0.126). Conclusions:Based on subjective scores and semi-quantitative indicators, 68Ga-PSMA PET/CT is superior to select β values of 600 and 700 for image reconstruction based on BSREMA. The SUV peak of small lesions is stable after PVC and the clinical value should be explored in further.
ABSTRACT
Objective:To prepare 68Ga-2-(4, 7-bis(carboxymethyl)-1, 4, 7-triazonan-1-yl)pentanedioic acid (NODAGA)-YHWYGYTPQNVI (GE11) and evaluate its feasibility of PET imaging for pancreatic cancer. Methods:GE11 peptide was conjugated with NODAGA and then labeled with 68Ga. The labeling yield, radiochemical purity, hydrophilicity, stability and specificity in vitro were determined. Human pancreatic cancer BxPC3 nude mice models ( n=9) were established. MicroPET imaging was then obtained after 30 and 90 min, and mice were sacrificed at 90 min to acquire the radioactivity distribution of main organs and tumors. Pair t test was used to analyze the data. Results:The labeling yield was (73.5±5.4)% and radiochemical purity was more than 98%. After incubation 120 min in mouse serum at 37 ℃, radiochemical purity was more than 92%. The uptake was specific in BxPC3 cell lines. MicroPET images showed that 68Ga-NODAGA-GE11 could accumulate quickly in tumor. Value of tumor uptake was significantly higher than that of normal pancreas at 90 min ((1.38±0.25) vs (0.49±0.07) %ID/g; t=12.67, P<0.05), and the radio-uptake of blood, muscle and bone was lower than that of tumor. Conclusions:68Ga-NODAGA-GE11 is easy to be prepared with high radiochemical purity and good stability, and can specifically target BxPC3 xenograft tumor. However, due to the high uptake in the kidneys and liver, the value of 68Ga-NODAGA-GE11 in PET imaging for pancreatic tumor needs further study.
ABSTRACT
Objective:To compare the diagnostic efficacy of 68Ga-prostate specific membrane antigen (PSMA)-11 PET/CT and 18F-fluorodeoxyglucose (FDG) PET/CT in TNM staging before radical prostatectomy. Methods:From July 2018 to December 2019, a total of 67 patients ((67.5±6.8) years) with prostate cancer diagnosed pathologically by radical surgery in Renji Hospital, School of Medicine, Shanghai Jiao Tong University were retrospectively enrolled. All patients underwent 68Ga-PSMA-11 PET/CT and 18F-FDG PET/CT whole-body scans before surgery. Results of PET/CT were compared with pathological diagnosis after surgery to compare the diagnostic efficiencies of 68Ga-PSMA-11 PET/CT and 18F-FDG PET/CT for preoperative TNM staging ( χ2 test). The differences of the maximum standardized uptake value (SUV max) in primary lesions between 2 imaging methods were compared by Mann-Whitney U test. Patients were divided into low-risk, intermediate-risk and high-risk for stratified analysis. Results:Among 67 patients, 9 were with low-risk, 19 were with intermediate-risk, 39 were with high-risk. For T staging, 59 (88.06%, 59/67) patients showed positive results by 68Ga-PSMA-11 PET/CT imaging, with median SUV max of 13.80(7.30, 22.40) for 67 patients; 31(46.27%, 31/67) patients showed positive results in 18F-FDG PET/CT imaging, with median SUV max of 4.00(3.10, 5.60) ( U=62, P<0.05). Stratifed analysis showed that the detection rate of 68Ga-PSMA-11 PET/CT was higher than that of 18F-FDG PET/CT in intermediate-risk patients (17/19 vs 6/19; χ2=4.920, P<0.05). Among 67 patients, 10 were diagnosed as N1 stage based on the pathological results. The sensitivities, specificities, accuracies, positive predictive values and negative predictive values of 68Ga-PSMA-11 PET/CT and 18F-FDG PET/CT for detecting positive regional lymph nodes were 6/10, 87.72%(50/57), 83.58%(56/67), 6/13, 92.59%(50/54) and 4/10, 89.47%(51/57), 82.09%(55/67), 4/10, 89.47%(51/57), respectively. 68Ga-PSMA-11 PET/CT detected 15 patients (22.39%, 15/67) with M1 stage, and 18F-FDG PET/CT identified 9 patients (13.43%, 9/67; χ2=35.436, P<0.05). Conclusions:As for T staging, the detection rate of 68Ga-PSMA-11 PET/CT in the intermediate-risk group is better than 18F-FDG PET/CT. In N and M staging, the detection rates of 68Ga-PSMA-11 PET/CT are higher than those of 18F-FDG PET/CT.
ABSTRACT
Objective:To synthesize a 68Ga-labeled oxalyldiaminopropionic acid (ODAP)-urea based prostate specific membrane antigen (PSMA) targeting probe, and evaluate its properties in vitro and in vivo. Methods:Ligand P151 was synthesized by solid-phase synthesis and its Ki value was determined. The ligand P151 was added into the mixture of 68GaCl 3 and NaOAc solution and was reacted at 95 ℃ for 10 min. The labeling yield and in vitro stability of 68Ga-P151 were determined by high performance liquid chromatography (HPLC). The lipid-water partition coefficient (log P) and cell binding ability were determined. The biodistribution of 68Ga-P151 in normal KM mice was determined. MicroPET imaging of 68Ga-P151 was carried out in prostate cancer 22Rv1 tumor-bearing mice and compared with 68Ga-PSMA 617. Independent sample t test was used to analyze the data. Results:P151 was successfully synthesized with the Ki of 0.58 nmol/L, the labeling yield more than 95% and the radiochemical purity more than 95%. After placement in saline or human serum albumin (HSA) solution at 37 ℃ for 2 h, the radiochemical purity of 68Ga-P151 was still more than 95%, indicating a good stability in vitro. The lipid-water partition coefficient (log P) of 68Ga-P151 was -2.65±0.17, indicating a good hydrophilicity. 68Ga-P151 specifically bound to PSMA in prostate cancer LNCaP cells with the uptake value of (0.83±0.04) percentage injection activity (%IA)/10 5 cells. Biodistribution of normal mice showed that 68Ga-P151 was mainly excreted through kidneys and other organs showed low uptake. MicroPET imaging of tumor-bearing mice showed the maximum standardized uptake value (SUV max: 0.79±0.23 vs 0.54±0.05; t=2.12), tumor/kidney ratio (2.04±0.65 vs 1.88±0.33; t=0.44) and tumor/muscle ratio (12.83±5.18 vs 6.95±1.63; t=2.17) between 68Ga-P151 and 68Ga-PSMA 617 were not significantly different (all P>0.05). Conclusions:68Ga-P151 can be prepared simply and labeled in high yield and show improved pharmacokinetic properties in vivo. The imaging of 68Ga-P151 on PSMA positive tumor is comparable to that of 68Ga-PSMA 617, making it a potential radiopharmaceutical for the diagnosis of prostate cancer.
ABSTRACT
Objective:To prepare a 68Ga labeled probe targeting integrin alpha M(CD11b) receptor, namely 68Ga-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid-Glycine-Arginine-Glutamate-Arginine-Glutamate-polyethylene glycol 11-1, 2, 4, 5-terazine/CD11b antibody-F(ab′) 2-trans-cyclooctene ( 68Ga-NOTA-Polypeptide-PEG 11-Tz/anti-CD11b-F(ab′) 2-TCO), and to explore its feasibility as a molecular probe for CD11b receptor through microPET imaging. Methods:Immunofluorescence was used to detect the expression of CD11b on the surface of RAW264.7 cell. CD11b specific monoclonal antibody (M1/70) was conjugated with TCO, and anti-CD11b-F(ab′) 2-TCO fragment was obtained. The ligand NOTA-Polypeptide-PEG 11-Tz was labeled with 68Ga, and its specific activity and radiochemical purity were detected. Pre-targeted cell binding experiment was conducted to evaluate the binding ability of molecular probe. CT26 colon cancer bearing mouse models were established, and then pre-targeted biodistribution and imaging experiments were performed. Immunohistochemical experiment was used to verify the expression of CD11b receptor in tumor. The one-way analysis of variance was used to compare the data. Results:The results of immunofluorescence demonstrated CD11b receptor was highly expressed on the surface of RAW264.7 cell. Anti-CD11b-F(ab′) 2-TCO fragment was verified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). 68Ga-NOTA-Polypeptide-PEG 11-Tz was successfully synthesized, with the labeling efficiency of 94.6%. The specific activity was 7.0-7.4 MBq/μg, and the radiochemical purity was higher than 95%. Pre-targeted cell binding experiment confirmed that the molecular probe bound to the CD11b receptor. The biodistribution and imaging experiments showed that the kidney radioactivity uptake was high at pre-targeted 4, 12 and 24 h intervals, which proved that probe was excreted through the urinary system. In addition, molecular probe had higher radioactive uptake at the tumor site, with the tumor/muscle ratios of 9.23±1.45, 12.53±1.36 and 10.74±1.11 ( F=848.8, P<0.05). When the radioligand was injected 1 h after the pre-positioned 12 h interval, the images contrast was the best, with the standardized uptake value (SUV) in tumor and muscle of 0.67±0.12, 0.09±0.04, respectively. Immunohistochemistry verified the highly expression of CD11b receptor in tumor. Conclusions:The pre-targeted molecular probe 68Ga-NOTA-Polypeptide-PEG 11-Tz/anti-CD11b-F(ab′) 2-TCO is successfully synthesized. The molecular probe has targeting ability for CD11b + colon cancer, and is expected to be used as a tracer targeting CD11b receptor in vivo.
ABSTRACT
Objective:To prepare a novel molecular imaging probe targeting angiotensin converting enzyme (ACE) 2 by using 68Ga labeled with 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-DX600, then the probe was evaluated in cervical cancer model by microPET/CT imaging. Methods:68Ga labeled DOTA-DX600 at 95 ℃, and the quality control, stability in vitro and lipid-water partition coefficient (log P) were tested. Tumor-bearing mouse models were constructed using stably transfected ACE2 highly expressed cervical cancer cells (Hela). The distribution and uptake of 68Ga-DOTA-DX600 in normal KM mice and tumor-bearing mice were determined by microPET/CT imaging, and the maximum standardized uptake value (SUV max) of the main organs and tumors were obtained by semi-quantitative analysis of the region of interest (ROI). Results:The preparation time of 68Ga-DOTA-DX600 was about 20 min, the specific activity of the probe was (18.74±3.72)×10 6 GBq/mol, the labeling rate was 82.3%, and the radiochemical purity was about 99% after purification. After placement in saline or 5% human serum albumin (HSA) solution at room temperature for 2 h, the radiochemical purity of the probe was more than 96%. The lipid-water partition coefficient (log P) was -2.44 ±0.04 ( n=3), which indicated as a good hydrophilicity. In normal KM mice, 68Ga-DOTA-DX600 metabolized faster in the blood and mainly distributed in the kidneys. The probe showed good tumor targeting ability in the tumor-bearing mice and the SUV max of the tumor were 0.25±0.01 and 0.21±0.01 at 30 min and 60 min after injection, respectively, and the tumor uptake was inhibited by DX600. Conclusion:68Ga-DOTA-DX600 can be obtained conveniently and fast and shows a good targeting ability to tumors, which provide potential application value for researches on targeting ACE2.
ABSTRACT
Objective:To compare the value of 68Ga-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid- D-Phe1-Tyr3-Thr8-octreotide (DOTATATE) and 18F-fluorodeoxyglucose (FDG) PET/CT imaging in the detection of bone metastasis in neuroendocrine neoplasm (NEN). Methods:From January 2014 to July 2019, 29 NEN patients (19 males, 10 females, age: 35-76 years) with bone metastasis who underwent 68Ga-DOTATATE and 18F-FDG PET/CT imaging within one month in Peking University Cancer Hospital & Institute were retrospectively enrolled. Patients were divided into Ki-67≤20% and Ki-67>20% groups according to the tumor proliferation activity, and osteolysis, osteogenesis and no change groups according to the CT findings of bone metastases. The differences of the number and radioactive uptake (maximum standardized uptake value (SUV max) ratio of bone lesion to normal bone (SUV T/B)) of detected bone metastases between 68Ga-DOTATATE and 18F-FDG PET/CT imaging were analyzed. χ2 and Mann-Whitney U tests were used to analyze the data. Results:The sensitivity of 68Ga-DOTATATE and 18F-FDG PET/CT imaging were 75.9%(22/29) and 82.8% (24/29) respectively, and there was no significant difference between the two modalities ( χ2=0.42, P>0.05). The numbers of cases with bone lesions detected by 68Ga-DOTATATE PET/CT imaging in pelvis, spine, ribs, proximal limbs, sternoclavicular scapula and skull were all higher than those of 18F-FDG PET/CT imaging (23, 22, 20, 14, 14, 10 vs 12, 19, 13, 11, 10, 6, respectively). The 68Ga-DOTATATE PET/CT imaging was significantly superior to 18F-FDG imaging in detecting bone metastases (9(3, 36) and 3(0, 18)) and SUV T/B(11.10(3.35, 22.30) and 1.60(1.05, 2.70); U values: 281.000, 77.000, both P<0.001). 68Ga-DOTATATE PET/CT imaging found more bone lesions in well differentiated NEN (Ki-67≤20%) group (11(2, 38) and 2(0, 13)) and osteogenic bone metastasis group (31(3, 100) and 3(0, 31); U values: 105.500, 69.500, both P<0.05). SUV T/B of 68Ga-DOTATATE PET/CT imaging was significantly higher than 18F-FDG PET/CT imaging in all subgroups ( U values: 3.000-22.000, all P<0.05). Conclusion:The 68Ga-DOTATATE PET/CT imaging is superior to 18F-FDG PET/CT imaging in the detection of bone metastasis in NEN.
ABSTRACT
Neuroendocrine neoplasms (NEN) are tumors that originate from neuroendocrine cells or peptidergic neurons. NEN can be found in a variety of organs with high heterogeneity in pathology and large difference in prognosis. Conventional imaging methods and pathological biopsy have important roles in the diagnosis of NEN, while both of them have limitations. Most NEN cells highly express several peptide receptors, especially somatostatin receptors (SSTR). Moreover, some of them have high glycolysis activity because of high proliferative activity. 68Ga-somatostatin analogs (68Ga-SSA) combined with 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging can comprehensively evaluate both the expression of SSTR and the activity of glycolysis in NEN, providing effective information for diagnosis, treatment, monitoring and prognosis. This review summarizes the current studies of combined 68Ga-SSA/18F-FDG PET/CT imaging in patients with NEN.