RESUMO
A wide variety of 18F-labeled PSMA-targeting PET radiotracers have been developed, including [18F]AlF-PSMA-11. As there is only limited data on the comparison with other 18F-labeled PSMA PET tracers, a comparative preclinical study between [18F]AlF-PSMA-11 and [18F]PSMA-1007 was conducted. Mice with varying PSMA expressing tumors (C4-2, 22Rv1 and PC-3, each n = 5) underwent two PET/CT scans with both [18F]AlF-PSMA-11 and [18F]PSMA-1007. Ten additional mice bearing C4-2 xenografts were subjected to ex vivo biodistribution with either [18F]AlF-PSMA-11 (n = 5) or [18F]PSMA-1007 (n = 5). Absolute SUVmean and SUVmax values were significantly higher for [18F]PSMA-1007 scans in both C4-2 tumors (p < 0.01) and 22Rv1 tumors (p < 0.01). In C4-2 xenograft bearing mice, the tumor-to-organ ratios did not significantly differ between [18F]AlF-PSMA-11 and [18F]PSMA-1007 for liver, muscle, blood and salivary glands (p > 0.05). However, in 22Rv1 xenograft bearing mice, all tumor-to-organ ratios were higher for [18F]AlF-PSMA-11 (p < 0.01). In healthy organs, [18F]PSMA-1007 uptake was higher in the liver, gallbladder, small intestines and glands. Biodistribution data confirmed the increased uptake in the heart, small intestines and liver with [18F]PSMA-1007. Absolute tumor uptake was higher with [18F]PSMA-1007 in all tumors. Tumor-to-organ ratios did not differ significantly in high PSMA expressing tumors, but were higher for [18F]AlF-PSMA-11 in low PSMA expressing tumors. Furthermore, [18F]PSMA-1007 showed higher uptake in healthy organs.
Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Animais , Humanos , Camundongos , Niacinamida/análogos & derivados , Oligopeptídeos , Tomografia por Emissão de Pósitrons , Distribuição TecidualRESUMO
BACKGROUND: Fluorine-18 (18F)-labelled prostate-specific membrane antigen (PSMA) offers several advantages over gallium-68 (68Ga) in terms of costs, yield, transport/distribution, and image resolution. OBJECTIVE: This trial investigates the new radiotracer 18F-PSMA-11 via a prospective, intraindividual crossover design. The trial was powered for noninferiority of 18F-PSMA-11 over 68Ga-PSMA-11 positron emission tomography (PET)/computed tomography (CT) in terms of the number of positive PET scans. Secondary endpoints were as follows: (1) superiority of 18F-PSMA-11 over 68Ga-PSMA-11 with respect to the number of positive PET scans, the total number of suspicious prostate cancer lesions, and the miPSMA expression score of corresponding lesions; (2) correlation of the PET/CT images with available follow-up data for 18F-PSMA-11 and 68Ga-PSMA-11; and (3) assessment of the interobserver variability. DESIGN, SETTING, AND PARTICIPANTS: Prostate cancer patients (primary or biochemical recurrence) were randomised in a double-blind crossover design whereby each patient received both 18F-PSMA-11 and 68Ga-PSMA-11 PET/CT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: All scans were reviewed and scored by three independent experienced nuclear physicians following the proposed guideline for the interpretation of PSMA-ligand PET/CT, as described by Eiber et al. RESULTS AND LIMITATIONS: In total, 82 patients were included for scan analyses. The primary endpoint was met: per patient, the proportions of positive scans rated by the three readers were 67%/67%, 65%/65%, and 73%/70% for 18F-PSMA-11/68Ga-PSMA-11 PET/CT. The miPSMA expression score was higher for 18F-PSMA-11 than for 68Ga-PSMA-11 for the reference reader. Follow-up data showed identical estimated sensitivity for both the 18F-PSMA-11 and the 68Ga-PSMA-11 scan (0.92, 0.83, and 0.92 for the three readers). A fair to good agreement among readers (at patient level) was obtained, which was demonstrated by a Light's kappa value of 0.59 for both tracers. CONCLUSIONS: The tracer 18F-PSMA-11 is noninferior to68Ga-PSMA-11. Superiority of 18F-PSMA-11 was limited to the miPSMA expression score, given by the reference reader. Inter-rater agreement was fair to good, and equal for both radiotracers. PATIENT SUMMARY: In this study, we compared two radiotracers: 18F-PSMA-11 and 68Ga-PSMA-11. We proved that 18F-PSMA-11 is not inferior to 68Ga-PSMA-11 for detecting prostate cancer and thus can be used as an alternative. Possible superiority of this tracer should be further investigated in specific subpopulations.
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Radioisótopos de Gálio , Neoplasias da Próstata , Estudos Cross-Over , Radioisótopos de Flúor , Isótopos de Gálio , Glutaratos , Humanos , Ligantes , Masculino , Ácidos Fosfínicos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estudos Prospectivos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologiaRESUMO
PURPOSE: In this study, we evaluated the impact of 18F-PSMA-11 PET/CT on the patient management plan in patients with primary or recurrent disease. Furthermore, a correlation between PET findings and other modalities was performed. PROCEDURES: In this prospective observational study, 60 prostate cancer patients (9 primary staging, 51 biochemical recurrence) were imaged with 18F-PSMA-11 PET/CT. Pre- and post-scan questionnaires were completed by the treating physician to observe changes in therapy intent. Follow-up data (histological confirmation, MRI imaging, and PSA values after radiotherapy without implementation of systemic therapy) was correlated with the 18F-PSMA-11 findings. RESULTS: The patient-based detection rate was 82% and a management change was seen in 52% of the cases. The heterogeneous characteristics of the included patients resulted in a widely varying treatment change, mostly originating from an increase of disease extent on 18F-PSMA-11 PET/CT. CONCLUSION: 18F-PSMA-11 PET/CT showed to be a highly promising method for the detection of prostate cancer lesions.
Assuntos
Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata , Masculino , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Antígeno Prostático Específico , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/terapia , Neoplasias da Próstata/patologia , Estudos Prospectivos , Radioisótopos de Gálio , Recidiva Local de Neoplasia/diagnóstico por imagemRESUMO
This two-part preclinical study aims to evaluate prostate specific membrane antigen (PSMA) as a valuable target for expression-based imaging applications and to determine changes in target binding in function of varying apparent molar activities (MAapp) of [18F]AlF-PSMA-11. For the evaluation of PSMA expression levels, male NOD/SCID mice bearing prostate cancer (PCa) xenografts of C4-2 (PSMA+++), 22Rv1 (PSMA+) and PC-3 (PSMA-) were administered [18F]AlF-PSMA-11 with a medium MAapp (20.24 ± 3.22 MBq/nmol). SUVmean and SUVmax values were respectively 3.22 and 3.17 times higher for the high versus low PSMA expressing tumors (p < 0.0001). To evaluate the effect of varying MAapp, C4-2 and 22Rv1 xenograft bearing mice underwent additional [18F]AlF-PSMA-11 imaging with a high (211.2 ± 38.9 MBq/nmol) and/or low MAapp (1.92 ± 0.27 MBq/nmol). SUV values showed a significantly increasing trend with higher MAapp. Significant changes were found for SUVmean and SUVmax between the high versus low MAapp and medium versus low MAapp (both p < 0.05), but not between the high versus medium MAapp (p = 0.055 and 0.25, respectively). The effect of varying MAapp was more pronounced in low expressing tumors and PSMA expressing tissues (e.g. salivary glands and kidneys). Overall, administration of a high MAapp increases the detection of low expression tumors while also increasing uptake in PSMA expressing tissues, possibly leading to false positive findings. In radioligand therapy, a medium MAapp could reduce radiation exposure to dose-limiting organs with only limited effect on radionuclide accumulation in the tumor.
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Regulação Neoplásica da Expressão Gênica , Glutamato Carboxipeptidase II/biossíntese , Glutaratos/farmacocinética , Glicoproteínas de Membrana/biossíntese , Ácidos Fosfínicos/farmacocinética , Neoplasias da Próstata/metabolismo , Complexo de Endopeptidases do Proteassoma/biossíntese , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transplante de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons , Neoplasias da Próstata/patologia , Ligação Proteica , Compostos Radiofarmacêuticos , Distribuição TecidualRESUMO
Recently, a 18F-labeled derivative of the widely used 68Ga-PSMA-11 was developed for PET imaging of prostate cancer. Although 18F-PSMA-11 has already been evaluated in a Phase I and Phase II clinical trial, preclinical evaluation of this radiotracer is important for further understanding its dynamic behavior. Saturation binding experiments were conducted by incubation of LNCaP cells with 18F-PSMA-11 or 68Ga-PSMA-11 for 1 h, followed by determination of the specific and aspecific binding. Mice bearing LNCaP or PC-3 xenografts each received ± 3.7 MBq 18F-PSMA-11 and 68Ga-PSMA-11 followed by dynamic acquisition of 2.5 h as well as ± 15 MBq 18F-FDG followed by static acquisition at 1 h post injection (p.i.). Uptake was evaluated by comparison of uptake parameters (SUVmean, SUVmax, TBRmean and TBRmax). Mice underwent ex vivo biodistribution where 18F-PSMA-11 activity was measures in excretory organs (kidneys, bladder and liver) as well as bone fragments (femur, humerus, sternum and skull) to evaluate bone uptake. The dissociation constant (Kd) of 18F-PSMA-11 and 68Ga-PSMA-11 was 2.95 ± 0.87 nM and 0.49 ± 0.20 nM, respectively. Uptake parameters were significantly higher in LNCaP compared to PC-3 xenografts for both 18F-PSMA-11 and 68Ga-PSMA-11, while no difference was found for 18F-FDG uptake (except for SUVmax). Tumor uptake of 18F-PSMA-11 showed a similar trend over time as 68Ga-PSMA-11, although all uptake parameter curves of the latter were considerably lower. When comparing early (60 min p.i.) to delayed (150 min p.i.) imaging for both radiotracers individually, TBRmean and TBRmax were significantly higher at the later timepoint, as well as the SUVmax of 68Ga-PSMA-11. The highest %ID/g was determined in the kidneys (94.0 ± 13.6%ID/g 1 h p.i.) and the bladder (6.48 ± 2.18%ID/g 1 h p.i.). No significant increase in bone uptake was seen between 1 and 2 h p.i. Both radiotracers showed high affinity for the PSMA receptor. Over time, all uptake parameters were higher for 18F-PSMA-11 compared to 68Ga-PSMA-11. Delayed imaging with the latter may improve tumor visualization, while no additional benefits could be found for late 18F-PSMA-11 imaging. Ex vivo biodistribution demonstrated fast renal clearance of 18F-PSMA-11 as well as no significant increase in bone uptake.
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Ácido Edético/análogos & derivados , Glutaratos/química , Oligopeptídeos/química , Ácidos Fosfínicos/química , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Linhagem Celular Tumoral , Ácido Edético/química , Fluordesoxiglucose F18/química , Isótopos de Gálio , Radioisótopos de Gálio , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Camundongos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/patologia , Distribuição TecidualRESUMO
BACKGROUND: Several scan parameters for PET imaging with 18F-PSMA-11 such as dosage, acquisition time and scan duration were evaluated to determine the most appropriate scan protocol, as well as the effect of furosemide administration on lesion visualization. Forty-four patients were randomly assigned to a dosage group (2.0 ± 0.2 or 4.0 ± 0.4 MBq/kg 18F-PSMA-11). All patients received a full-body PET/CT 1 h and 3 h after radiotracer injection with a scan duration of 3 min/bed position. For comparison of the scan duration, images were reconstructed for 1.5 and 3 min/bed position. Patients were intravenously administered 0.5 mg/kg furosemide with a maximum dose of 40 mg. To evaluate the furosemide effect, 22 additional patients were recruited and received one full-body PET/CT 1 h after administration of 2.0 ± 0.2 MBq/kg 18F-PSMA-11 with a scan duration of 3 min/bed position. To this group, no furosemide was administered. Images were scored on image quality using a 7-point scale and each suspicious lesion was described. To assess interrater reliability, two nuclear physicians scored all scans independently and described all observed suspicious lesions. RESULTS: The 4 MBq/kg group received for all reconstructed images (60 min p.i., 1.5 and 3 min/bed position and 180 min p.i., 1.5 and 3 min/bed position) the highest median image quality score compared to the 2 MBq/kg group (p values < 0.01). When comparing all reconstructed images, the highest image quality score was given to images at 60 min p.i., 3 min/bed position for both dosage groups (score 5 and 6 for 2 and 4 MBq/kg, respectively). The addition of furosemide administration decreased the interference score with one point (p = 0.01106) and facilitated the evaluation of lesions in proximity to the ureters. The interrater reliability for the comparison of each lesion separately after more than 40 18F-PSMA-11 scan readings showed an increasing κ value from 0.78 (95% CI, 0.65-0.92) to 0.94 (95% CI, 0.87-1). CONCLUSION: Although the results indicate an administered activity of 4.0 ± 0.4 MBq/kg, preference will be given to 2.0 ± 0.2 MBq/kg due to the small difference in absolute score (max 1 point) and the ALARA principle. For evaluation of lesions in proximity to the ureters, the co-administration of a diuretic can be useful. The increase of the κ value from 0.78 to 0.94 suggests a learning curve in the interpretation of 18F-PSMA-11 images. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03573011. Retrospectively registered 28 June 2018.
RESUMO
BACKGROUND: Glioblastoma (GB) is the most common primary malignant brain tumor. Standard medical treatment consists of a maximal safe surgical resection, subsequently radiation therapy (RT) and chemotherapy with temozolomide (TMZ). An accurate definition of the tumor volume is of utmost importance for guiding RT. In this project we investigated the feasibility and treatment response of subvolume boosting to a PET-defined tumor part. METHOD: F98 GB cells inoculated in the rat brain were imaged using T2- and contrast-enhanced T1-weighted (T1w) MRI. A dose of 20 Gy (5 × 5 mm2) was delivered to the target volume delineated based on T1w MRI for three treatment groups. Two of those treatment groups received an additional radiation boost of 5 Gy (1 × 1 mm2) delivered to the region either with maximum [18F]FET or [18F]FAZA PET tracer uptake, respectively. All therapy groups received intraperitoneal (IP) injections of TMZ. Finally, a control group received no RT and only control IP injections. The average, minimum and maximum dose, as well as the D90-, D50- and D2- values were calculated for nine rats using both RT plans. To evaluate response to therapy, follow-up tumor volumes were delineated based on T1w MRI. RESULTS: When comparing the dose volume histograms, a significant difference was found exclusively between the D2-values. A significant difference in tumor growth was only found between active therapy and sham therapy respectively, while no significant differences were found when comparing the three treatment groups. CONCLUSION: In this study we showed the feasibility of PET guided subvolume boosting of F98 glioblastoma in rats. No evidence was found for a beneficial effect regarding tumor response. However, improvements for dose targeting in rodents and studies investigating new targeted drugs for GB treatment are mandatory.
Assuntos
Neoplasias Encefálicas/radioterapia , Modelos Animais de Doenças , Glioblastoma/radioterapia , Tomografia por Emissão de Pósitrons , Radioterapia Guiada por Imagem/métodos , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Estudos de Viabilidade , Feminino , Glioblastoma/metabolismo , Nitroimidazóis/metabolismo , Nitroimidazóis/uso terapêutico , Compostos Radiofarmacêuticos/metabolismo , Compostos Radiofarmacêuticos/uso terapêutico , Dosagem Radioterapêutica , Ratos Endogâmicos F344 , Resultado do Tratamento , Carga Tumoral , Tirosina/análogos & derivados , Tirosina/metabolismo , Tirosina/uso terapêuticoRESUMO
Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer. Many PSMA analog radiotracers for PET/CT prostate cancer staging have been developed, such as 68Ga-PSMA-11. This radiotracer has achieved good results in multiple clinical trials, but because of the superior imaging characteristics of 18F-fluoride, 18F-PSMA-11 was developed. The aim of this study was to evaluate the administration safety and radiation dosimetry of 18F-PSMA-11. Methods: Six patients (aged 62-68 y; mean, 66 ± 2 y) with suspected prostate cancer recurrence after previous treatment were administered 2 MBq of 18F-PSMA-11 per kilogram of body weight and then underwent low-dose PET/CT imaging at 0, 20, 50, 90, and 300 min after injection. To evaluate the safety of administration, vital parameters were monitored. To assess toxicity, full blood count and biochemical parameters were determined. According to the latest International Commission on Radiological Protection recommendations, radiation dosimetry analysis was performed using IDAC-Dose 2.1. For blood activity measurement, small samples of venous blood were collected at various time points after injection. The unbound 18F-fluoride fraction was determined in plasma at 20, 50, and 90 min after administration to evaluate the defluorination rate of 18F-PSMA-11. Results: After injection, 18F-PSMA-11 cleared rapidly from the blood. At 5 h after injection, 29.0% ± 5.9% of the activity was excreted in urine. The free 18F fraction in plasma increased from 9.7% ± 1.0% 20 min after injection to 22.2% ± 1.5% 90 min after injection. The highest tracer uptake was observed in kidneys, bladder, spleen, and liver. No study drug-related adverse events were observed. The calculated mean effective dose was 12.8 ± 0.6 µSv/MBq. Conclusion:18F-PSMA-11 can be safely administered and results in a mean effective dose of 12.8 ± 0.6 µSv/MBq. Therefore, the total radiation dose is lower than for other PSMA PET agents and in the same range as 18F-DCFPyL.
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Glutaratos/farmacocinética , Ácidos Fosfínicos/farmacocinética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Idoso , Glutaratos/química , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Fosfínicos/química , Radiometria , Distribuição TecidualRESUMO
The use of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) as a positron emission tomography (PET) tracer for brain tumor imaging might have some limitations because of the relatively low affinity for the L-type amino acid transporter 1 (LAT1). To assess the stereospecificity and evaluate the influence of aromatic ring modification of phenylalanine LAT1 targeting tracers, six different fluoroalkylated phenylalanine analogues were synthesized. After in vitro Ki determination, the most promising compound, 2-[18F]-2-fluoroethyl-L-phenylalanine (2-[18F]FELP), was selected for further evaluation and in vitro comparison with [18F]FET. Subsequently, 2-[18F]FELP was assessed in vivo and compared with [18F]FET and [18F]FDG in a F98 glioblastoma rat model. 2-[18F]FELP showed improved in vitro characteristics over [18F]FET, especially when the affinity and specificity for system L is concerned. Based on our results, 2-[18F]FELP is a promising new PET tracer for brain tumor imaging.
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Glioblastoma/metabolismo , Glioblastoma/patologia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/metabolismo , Tirosina/análogos & derivados , Animais , Apoptose , Proliferação de Células , Feminino , Glioblastoma/diagnóstico por imagem , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/genética , Ratos , Células Tumorais Cultivadas , Tirosina/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Introduction: An in vivo determination of bile acid hepatobiliary transport efficiency can be of use in liver disease and preclinical drug development. Given the increased interest in bile acid Positron Emission Tomography- (PET-) imaging, a further understanding of the impact of 18-fluorine substitution on bile acid handling in vitro and in vivo can be of significance. Methods: A number of bile acid analogues were conceived for nucleophilic substitution with [18F]fluoride: cholic acid analogues of which the 3-, 7-, or 12-OH function is substituted with a fluorine atom (3α-[18F]FCA; 7ß-[18F]FCA; 12ß-[18F]FCA); a glycocholic and chenodeoxycholic acid analogue, substituted on the 3-position (3ß-[18F]FGCA and 3ß-[18F]FCDCA, resp.). Uptake by the bile acid transporters NTCP and OATP1B1 was evaluated with competition assays in transfected CHO and HEK cell lines and efflux by BSEP in membrane vesicles. PET-scans with the tracers were performed in wild-type mice (n = 3 per group): hepatobiliary transport was monitored and compared to a reference tracer, namely, 3ß-[18F]FCA. Results: Compounds 3α-[18F]FCA, 3ß-[18F]FGCA, and 3ß-[18F]FCDCA were synthesized in moderate radiochemical yields (4-10% n.d.c.) and high radiochemical purity (>99%); 7ß-[18F]FCA and 12ß-[18F]FCA could not be synthesized and included further in this study. In vitro evaluation showed that 3α-FCA, 3ß-FGCA, and 3ß-FCDCA all had a low micromolar Ki-value for NTCP, OATP1B1, and BSEP. In vivo, 3α-[18F]FCA, 3ß-[18F]FGCA, and 3ß-[18F]FCDCA displayed hepatobiliary transport with varying efficiency. A slight yet significant difference in uptake and efflux rate was noticed between the 3α-[18F]FCA and 3ß-[18F]FCA epimers. Conjugation of 3ß-[18F]FCA with glycine had no significant effect in vivo. Compound 3ß-[18F]FCDCA showed a significantly slower hepatic uptake and efflux towards gallbladder and intestines. Conclusion: A set of 18F labeled bile acids was synthesized that are substrates of the bile acid transporters in vitro and in vivo and can serve as PET-biomarkers for hepatobiliary transport of bile acids.
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Ácidos e Sais Biliares/química , Eliminação Hepatobiliar , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/síntese química , Animais , Ácidos e Sais Biliares/síntese química , Ácidos e Sais Biliares/metabolismo , Transporte Biológico , Células CHO , Proteínas de Transporte/metabolismo , Cricetulus , Radioisótopos de Flúor , Células HEK293 , Humanos , Glicoproteínas de Membrana/metabolismo , Camundongos , Estrutura Molecular , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Simportadores/metabolismoRESUMO
BACKGROUND: Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with 18F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo. METHODS: In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (< 1%) conditions: control (100 µL PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 µl NaCl 0.9% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. 18F-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation). RESULTS: A T/B ≥ 3.59 on pre-treatment 18F-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3%, specificity 71.4%). Radiation was less effective in hypoxic tumors (T/B ≥ 3.59) compared to normoxic tumors (T/B < 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth. CONCLUSIONS: Tumor tissue hypoxia as measured with 18F-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation.
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Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tolerância a Radiação , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Nimorazol/farmacologia , Nitroimidazóis , Compostos Radiofarmacêuticos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVES: We report a reproducible automated radiosynthesis for large scale batch production of clinical grade Al[18F]PSMA-11. METHODS: A SynthraFCHOL module was optimized to synthesize Al[18F]PSMA-11 by Al[18F]-chelation. Results Al[18F]PSMA-11 was synthesized within 35min in a yield of 21 ± 3% (24.0 ± 6.0GBq) and a radiochemical purity > 95%. Batches were stable for 4h and conform the European Pharmacopeia guidelines. CONCLUSIONS: The automated synthesis of Al[18F]PSMA-11 allows for large scale production and distribution of Al[18F]PSMA-11.
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INTRODUCTION: Hepatobiliary transport mechanisms are crucial for the excretion of substrate toxic compounds. Drugs can inhibit these transporters, which can lead to drug-drug interactions causing toxicity. Therefore, it is important to assess this early during the development of new drug candidates. The aim of the current study is the (radio)synthesis, in vitro and in vivo evaluation of a technetium labeled chenodeoxycholic and cholic acid analogue: [(99m)Tc]-DTPA-CDCA and [(99m)]Tc-DTPA-CA, respectively, as biomarker for disturbed transporter functionality. METHODS: [99mTc]-DTPA-CDCA([(99m)Tc]-3a) and [99mTc]-DTPA-CA ([(99m)Tc]-3b) were synthesized and evaluated in vitro and in vivo. Uptake of both tracers was investigated in NTCP, OCT1, OATP1B1, OATP1B3 transfected cell lines. Km and Vmax values were determined and compared to [(99m)Tc]-mebrofenin ([(99m)Tc]-MEB). Efflux was investigated by means of CTRL, MRP2 and BSEP transfected inside-out vesicles. Metabolite analysis was performed using pooled human liver S9. Wild type (n=3) and rifampicin treated (n=3) mice were intravenously injected with 37MBq of tracer. After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of heart, liver, gallbladder and intestines were obtained. RESULTS: We demonstrated that OATP1B1 and OATP1B3 are the involved uptake transporters of both compounds. Both tracers show a higher affinity compared to [(99m)Tc]-MEB, but are in a similar range as endogenous bile acids for OATP1B1 and OATP1B3. [(99m)Tc]-3a shows higher affinities compared to [(99m)Tc]-3b. Vmax values were lower compared to [(99m)Tc]-MEB, but in the same range as endogenous bile acids. MRP2 was identified as efflux transporter. Less than 7% of both radiotracers was metabolized in the liver. In vitro results were confirmed by in vivo results. Uptake in the liver and efflux to gallbladder + intestines and urinary bladder of both tracers was observed. Transport was inhibited by rifampicin. CONCLUSION: The involved transporters were identified; both tracers are taken up in the hepatocytes by OATP1B1 andOATP1B3 with Km and Vmax values in the same range as endogenous bile acids and are secreted into bile canaliculi via MRP2. Dynamic small-animal SPECT imaging can be a useful noninvasive method of visualizing and quantifying hepatobiliary transporter functionality and disturbances thereof in vivo, which could predict drug pharmacokinetics.
Assuntos
Ácido Quenodesoxicólico/química , Ácido Cólico/química , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Tecnécio/química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Transporte Biológico , Linhagem Celular , Técnicas de Química Sintética , Ácido Quenodesoxicólico/síntese química , Ácido Quenodesoxicólico/metabolismo , Ácido Cólico/síntese química , Ácido Cólico/metabolismo , Feminino , Humanos , Marcação por Isótopo , Camundongos , Radioquímica , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de SolutoRESUMO
BACKGROUND: Carrier-added [(123)I]-2-iodo-D-phenylalanine (CA [(123)I]-2-I-D-Phe) was previously found to have a preferential retention in tumors with a high tumor background contrast in animal models. A previous human dosimetry study demonstrated a favorable biodistribution and radiation burden in human subjects. AIM: The aim of this study was to investigate the potential of CA [(131)I]-2-I-D-Phe as an agent for radionuclide therapy. METHODS: Sixty (60) nude athymic mice were inoculated subcutaneously with firefly luciferase-transduced R1M rhabdomyosarcoma cells. The mice in the therapy group were injected intravenously (i.v.) with 148 MBq [(131)I]-2-I-D-Phe (432 GBq/mmol) in kit solution. Controls were injected with kit solution without radioactivity, with physiological saline, or with 148 MBq [(131)I](-) in physiological saline. Tumor growth was quantified using bioluminescent imaging and caliper measurements. RESULTS: [(131)I]-2-I-D-Phe clearly reduced tumor growth in the treated mice compared with the control groups. A tumor growth-rate reduction of at least 33% was found for mice receiving a therapeutic dose. There were no serious adverse side-effects of the therapy. CONCLUSIONS: In conclusion, i.v. injection of CA 148 MBq [(131)I]-2-I-D-Phe specifically reduces tumor growth in athymic nude mice without relevant side-effects on the animals' health.
Assuntos
Radioisótopos do Iodo , Luciferases/metabolismo , Fenilalanina/análogos & derivados , Compostos Radiofarmacêuticos , Rabdomiossarcoma/diagnóstico por imagem , Animais , Humanos , Medições Luminescentes , Camundongos , Camundongos Nus , Cintilografia , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: Non carrier added (NCA) 2-[(18)F]fluoromethyl-l-phenylalanine is currently used in a Phase I study. Improvement of the stability of the fluorobenzyl analogue, very sensitive to defluorination and hydrolysis, during the synthetic route and in the radiopharmaceutical formulation was devised. METHODS: The protected brominated precursor was synthesised in three steps. The labelling with [(18)F(-)] occurred in acetonitrile using K(2)CO(3)/K(2.2.2) (120 degrees C, 5 min). NCA 3-(2-[(18)F(-)]Fluoromethyl-phenyl)-2-tert-butoxycarbonylamino-propionic acid tert-butyl ester recovered from HPLC was submitted to deprotection in TFA/CH(2)Cl(2) in the presence of CaCl(2). After evaporation and adsorption on a mini C18 column, the tracer was recovered in 4 ml of H(2)O. Appropriate amounts of CaCl(2) and NaCl solutions were added for isotonic formulation, and this solution was sterilised by a 0.2-microm Cathivex filter. Shelf-life stability in the presence of Ca(2+) and Mg(2+) ions was studied. Stereoisomeric purity was checked by chiral HPLC. RESULTS: The labelling showed a reproducible labelling yield of at least 90%. The followed strategy and the presence of Ca(2+) ions during deprotection, minimizing the loss of [(18)F(-)] from the labile fluorobenzyl group, allowed to obtain a decay-corrected yield of 75%. No racemisation was observed. The radiopharmaceutical formulation containing 0.04 M CaCl(2) allows a shelf-life of about 6 h without significant radiodefluorination. CONCLUSION: The described synthetic route yields 40% of radiochemical pure NCA 2-[(18)F]fluoromethyl-l-phenylalanine within 105 min. A solution was found to reduce considerably the radiodefluorination. Addition of CaCl(2) prior to deprotection limits the loss of radiofluoride to less than 10%. The calcium ions present in the final radiopharmaceutical formulation (0.04 M) assure a shelf-life of at least 6 h.
Assuntos
Química Farmacêutica/métodos , Radioisótopos de Flúor/química , Fluorbenzenos/química , Fenilalanina/análogos & derivados , Cálcio/química , Portadores de Fármacos , Estabilidade de Medicamentos , Marcação por Isótopo/métodos , Fenilalanina/química , Compostos Radiofarmacêuticos/síntese químicaRESUMO
The aim of this study was the comparison of the tumour uptake and the long-term retention of [(123)I]-2-I-L-phenylalanine and [(123)I]-2-I-D-phenylalanine with those of [(123)I]-2-I-L-tyrosine and [(123)I]-2-I-D-tyrosine in R1M rhabdomyosarcoma tumour-bearing rats. The biodistribution of the radioactivity as a function of time in R1M tumour-bearing rats was measured by planar gamma camera imaging (dynamic and static). If dissection was applied, the activity in the tumours and tissues of interest was measured by gamma counting. [(123)I]-2-iodo-L-phenylalanine, [(123)I]-2-iodo-D-phenylalaine, [(123)I]-2-I-L-tyrosine showed a considerable tumour uptake reaching a maximum between 10 and 30 min. At 30 min p.i. the differential uptake ratio values of this uptake were, respectively, 2.1, 2.3, 2.5 and 1.7. The activity in the tumour was shown to be related to a tumour cell uptake and not to an increased blood pool activity. All the tracers showed a clearance from the blood to the bladder without renal retention. At longer times both L- and D- [(123)I]-2-I-tyrosine were cleared for a large part from the tumours and the body. [(123)I]-2-I-L-Phe and [(123)I]-2-I-D-Phe showed a considerable and equal retention in the tumours: as compared with 0.5 h, 91% at 24 h and 80% at 48 h. This was related to the longer retention of activity in the blood pool noticed for these compounds (81% at 24 h and 65% at 48 h). The tumour-to-background ratio increased with 25% at those longer times. At short times all the tracers were taken up to a considerable extent in the tumours. In the R1M-bearing Wag/Rij rat model only [(123)I]-2-I-L-phenylalanine and [(123)I]-2-I-D-phenylalanine showed an especially high retention at long times without any significant difference between the enantiomers.
Assuntos
Radioisótopos do Iodo/farmacocinética , Fenilalanina/farmacocinética , Rabdomiossarcoma/metabolismo , Tirosina/farmacocinética , Animais , Farmacocinética , Ratos , Rabdomiossarcoma/diagnósticoRESUMO
PURPOSE: Several authors have shown in animal studies that D-enantiomeric amino acid analogues can have better tumour imaging properties compared to their L-analogues. In our group, the D and L isomers of 2-[I]iodo-phenylalanine were identified as tumour-specific tracers in rat and mouse tumour models, with an advantage for the D-isomer. Here we compare, intra-individually, the normal biodistribution and dosimetry of both tracers in healthy human subjects. METHODS: Five male volunteers received both the L- and D-enantiomers, ranging from 84 to 114 MBq, with a 1 week interval between the tracers, allowing intra-individual comparison. Whole-body scans were performed and blood and urine samples were collected and analysed up to 24 h. Dosimetry was calculated using OLINDA 1.0 software. RESULTS: The biodistributions of the tracers are comparable as both show a moderate uptake in heart and the liver, a marked uptake in muscle tissue and clearance via the renal system. However, due to faster clearance, from 2.5 h, the uptake of the D-enantiomer was significantly lower compared to the L-isomer in all organs. The radiation dose estimations showed an effective dose of, respectively, 0.0120+/-0.0020 mSv x Bq(-1) and 0.0106+/-0.0038 mSv x Bq(-1) for 2-123I-L-Phe and 2-123I-D-Phe (P=0.18). In both cases the organ receiving the highest dose was the bladder wall. CONCLUSION: Both 2-123I-L-Phe and 2-123I-D-Phe show comparable moderate uptake in all organs. 2-123I-D-Phe is the more promising tracer, as it shows a faster clearance resulting in a lower dose and a lower background, favouring tumour imaging with respect to the tumour/background ratio.
Assuntos
Fenilalanina/análogos & derivados , Contagem Corporal Total , Adulto , Humanos , Isomerismo , Masculino , Taxa de Depuração Metabólica , Especificidade de Órgãos , Fenilalanina/análise , Fenilalanina/química , Fenilalanina/farmacocinética , Compostos Radiofarmacêuticos/análise , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Sensibilidade e Especificidade , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
PURPOSE: 123I-2-iodo-tyrosine (123I-2IT) has been identified as a promising new amino acid tracer in animals. Uptake is mediated by LAT1 transport, which is increased in tumour cells. In this study we present the human biodistribution and first clinical results in glioma patients. METHODS: For the biodistribution study, six male volunteers received 60-95 MBq 123I-2IT. Whole-body scans and blood and urine samples were obtained up to 24 h after injection; dosimetry was calculated using OLINDA 1.0 software. Initial clinical evaluation of 123I-2IT SPECT was performed in 35 patients with suspected or known glioma, either as primary diagnosis or for detection of recurrence. Tumour-to-background (T/B) ratios were calculated for semi-quantitative analysis. The results were correlated with clinical and MRI follow-up data or histology. RESULTS: 123I-2IT showed both renal and intestinal clearance. Bladder (0.12 mGy/MBq) and small intestine (0.03 mGy/MBq) received the highest absorbed doses. The effective dose equivalent and effective dose were estimated at 0.020 and 0.016 mSv/MBq, respectively. In patients, 123I-2IT SPECT did not differentiate between neoplastic and non-neoplastic lesions after an indeterminate MRI. In follow-up of known glioma, 13/15 patients with disease recurrence had increased T/B values (range 1.39-3.91). Out of seven recurrence-negative patients, two showed an important increase in T/B, in one case due to radionecrosis (T/B 1.59) and in the other probably due to residual but stable disease (T/B 2.07). CONCLUSION: 123I-2IT has a favourable biodistribution for a tumour imaging agent. It shows increased uptake in central nervous system glioma and is potentially useful in the follow-up of glioma patients.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Glioma/diagnóstico por imagem , Glioma/metabolismo , Monoiodotirosina/farmacocinética , Adolescente , Carga Corporal (Radioterapia) , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Especificidade de Órgãos , Projetos Piloto , Doses de Radiação , Radiometria , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
Due to its high affinity for [(125)I]Angiotensin IV, cystinyl aminopeptidase (CAP) has recently been assigned as the 'angiotensin AT(4) receptor'. Since the aminopeptidase N (AP-N) activity is also susceptible to inhibition by Angiotensin IV, it might represent an additional target for this peptide. Based on [(125)I]Angiotensin IV binding and catalytic activity measurements, we compared the ligand interaction properties of recombinant human CAP and human AP-N. Both enzymes displayed distinct pharmacological profiles. Although their activity is inhibited by Angiotensin IV and LVV-hemorphin 7, both peptides are more potent CAP-inhibitors. On the other hand, substance P and l-methionine have a higher potency for AP-N. High affinity binding of [(125)I]Angiotensin IV to CAP occurs in the presence of chelators but not to AP-N in either the absence or presence of chelators. These differences were exploited to determine whether CAP and/or AP-N are present in different cell lines (CHO-K1, COS-7, HEK293, SK-N-MC and MDBK). We provide evidence that CAP predominates in these cell lines and that, comparatively, CHO-K1 cells display the highest level of this enzyme.
Assuntos
Angiotensina II/análogos & derivados , Antígenos CD13/metabolismo , Cistinil Aminopeptidase/metabolismo , Inibidores Enzimáticos/metabolismo , Receptores de Angiotensina/metabolismo , Angiotensina II/metabolismo , Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina , Animais , Ligação Competitiva , Antígenos CD13/antagonistas & inibidores , Antígenos CD13/genética , Células CHO , Células COS , Membrana Celular/metabolismo , Chlorocebus aethiops , Cricetinae , Cricetulus , Cistinil Aminopeptidase/antagonistas & inibidores , Cistinil Aminopeptidase/genética , Cães , Inibidores Enzimáticos/farmacologia , Humanos , Radioisótopos do Iodo , Cinética , Ligantes , Ligação Proteica , Proteínas Recombinantes/metabolismo , TransfecçãoRESUMO
Various radiolabeled amino acids show promising results in tumor detection, as applied in the management of cancer patients. We synthesized the precursor 2-iodo-L-phenylalanine for easier kit labeling of [123/125I]- 2-iodo-L-phenylalanine, using the Cu1+ -assisted nucleophilic halogen exchange. Precursor synthesis was optimized by experimental design: Eight parameters were initially screened by a quarter fractional design. The resulting most important parameters (i.e., temperature, CuSO4, NaI) were further optimized using a full three-factor, three-level factorial design. The final conclusion for the optimal values for temperature, reaction time, and concentration of 2-bromo-L-phenylalanine, NaI, CuSO4, SnSO4, C6H6O7, and C7H6O4 were 180 degrees C, 24 hours, 61 mM, 485 mM, 10 mM, 90 mM, 90 mM, and 100 mM, respectively. The yield was increased from 39% to consistently more than 74% 2-iodo-L-phenylalanine. Structure confirmation and quality control was performed by 1H-NMR, mass spectroscopy (MS), and high-performance liquid chromatography (HPLC) (reverse phase [RP] and chiral). No phenylalanine-related impurities or racemization was detected. Subsequent radioiodination of the obtained 2-iodo-L-phenylalanine was performed in kit conditions with n.c.a. Na123/125I, resulting in a labeling yield of > 98%. After Ag-membrane filtration, a radiochemical purity of > 99% was obtained. The Cu1+ -assisted nucleophilic exchange reaction allows both routine kit preparation and "cold" synthesis of 2-iodo-L-phenylalanine from 2-bromo-L-phenylalanine. The reaction presents an interesting alternative for a cumbersome multistep, stereo-specific synthesis.