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Purpose 4-Borono-2-[18F]fluoro-l-phenylalanine ([18F]FBPA) synthesized with [18F]F2, produced using the 18O(p, n)18F reaction, has been reported for increasing radioactivity. However, a dedicated system and complex procedure is required to reuse the costly [18O]O2 gas; also, the use of [18F]F2 as a labeling agent reduces the labeling rate and radiochemical purity. We developed a stable and practical method for [18F]FBPA synthesis by combining [18F]F2, produced using a [18O]O2 single-use system, and a [18F]CH3COOF labeling agent. Methods The produced [18F]F2 was optimized, and then [18F]FBPA was synthesized. For passivation of the target box, 0.5% F2 was pre-irradiated in argon. Gaseous products were discarded; the target box was filled with [18O]O2 gas, and then irradiated (first irradiation). Then, the [18O]O2 gas was discarded, 0.05–0.08% F2 in argon was fed into the target box, and it was again irradiated (second irradiation). The [18F]F2 obtained after this was passed through a CH3COONa column, converting it into the [18F]CH3COOF labeling agent, which was then used for [18F]FBPA synthesis. Results The mean amount of as-obtained [18F]F2 was 55.0 ± 3.3 GBq and that of as-obtained [18F]CH3COOF was 21.6 ± 1.4 GBq after the bombardment. The radioactivity and the radiochemical yield based on [18F]F2 of [18F]FBPA were 4.72 ± 0.34 GBq and 12.2 ± 0.1%, respectively. The radiochemical purity and molar activity were 99.3 ± 0.1% and 231 ± 22 GBq/mmol, respectively. Conclusion We developed a method for [18F]FBPA production, which is more stable and practical compared with the method using [18O]O2 gas-recycling and [18F]F2 labeling agent.

Purpose Fibroblast activation protein (FAP), which has high expression in cancer-associated fibroblasts of epithelial cancers, can be used as a theranostic target. Our previous study used 64Cu and 225Ac-labelled FAP inhibitors (FAPI-04) for a FAP-expressing pancreatic cancer xenograft imaging and therapy. However, the optimal therapeutic radionuclide for FAPI needs to be investigated further. In this study, we evaluated the therapeutic effects of beta-emitter (177Lu)-labelled FAPI-46 and alpha-emitter (225Ac)-labelled FAPI-46 in pancreatic cancer models. Methods PET scans (1 h post injection) were acquired in PANC-1 xenograft mice (n = 9) after the administration of [18F]FAPI-74 (12.4 ± 1.7 MBq) for the companion imaging. The biodistribution of [177Lu]FAPI-46 and [225Ac]FAPI-46 were evaluated in the xenograft model (total n = 12). For the determination of treatment effects, [177Lu]FAPI-46 and [225Ac]FAPI-46 were injected into PANC-1 xenograft mice at different doses: 3 MBq (n = 6), 10 MBq (n = 6), 30 MBq (n = 6), control (n = 4) for [177Lu]FAPI-46, and 3 kBq (n = 3), 10 kBq (n = 2), 30 kBq (n = 6), control (n = 7) for [225Ac]FAPI-46. Tumour sizes and body weights were followed. Results [18F]FAPI-74 showed rapid clearance by the kidneys and high accumulation in the tumour and intestine 1 h after administration. [177Lu]FAPI-46 and [225Ac]FAPI-46 also showed rapid clearance by the kidneys and relatively high accumulation in the tumour at 3 h. Both [177Lu]FAPI-46 and [225Ac]FAPI-46 showed tumour-suppressive effects, with a mild decrease in body weight. The treatment effects of [177Lu]FAPI-46 were relatively slow but lasted longer than those of [225Ac]FAPI-46. Conclusion This study suggested the possible application of FAPI radioligand therapy in FAP-expressing pancreatic cancer. Further evaluation is necessary to find the best radionuclide with shorter half-life, as well as the combination with therapies targeting tumour cells directly.

Background Fibroblast activation protein (FAP) is overexpressed in the stroma of many types of cancer. [18F]AlF-FAPI-74 is a positron emission tomography tracer with high selectivity for FAP, which has already shown high accumulation within human tumors in clinical studies. However, [18F]AlF-FAPI-74 radiosynthesis has not been optimized using an automated synthesizer. Herein, we report a one-pot and one-step automated radiosynthesis method using a multi purpose synthesizer. Results Radiosynthesis of [18F]AlF-FAPI-74 was performed using a cassette-type multi purpose synthesizer CFN-MPS200. After the recovery rate of trapped [18F]fluoride onto the anion-exchange cartridge using a small amount of eluent was investigated manually, a dedicated [18F]AlF-FAPI-74 synthesis cassette and synthesis program for one-pot and one-step fluorination was developed. The solutions for the formulation of [18F]AlF-FAPI-74 synthesized using this were evaluated to obtain stable radiochemical purity. The recovery rate of [18F]fluoride with only 300 µL of eluent ranged 90 ± 9% by introduction from the male side and elution from the female side of the cartridge. In automated synthesis, the eluted [18F]fluoride and precursor solution containing aluminum chloride were mixed; then, fluorination was performed in a one-pot and one-step process at room temperature for 5 min, followed by 15 min at 95 °C. As a result, the radioactivity of [18F]AlF-FAPI-74 was 11.3 ± 1.1 GBq at the end of synthesis from 32 to 40 GBq of [18F]fluoride, and its radiochemical yield was 37 ± 4% (n = 10). The radiochemical purity at the end of the synthesis was ≥ 97% for all formulation solutions. When the diluent was saline, the radiochemical purity markedly decreased after 4 h of synthesis. In contrast, with phosphate-buffered saline (pH 7.4) or 10 mM phosphate-buffered saline (pH 6.7) containing 100 mg of sodium ascorbate, the radiochemical purity was stable at 97%. Non-radioactive AlF-FAPI-74 and total impurities, including non-radioactive AlF-FAPI-74, were 0.3 ± 0.1 µg/mL and 2.8 ± 0.6 µg/mL. Ethanol concentration and residual DMSO were 5.5 ± 0.2% and 21 ± 6 ppm, respectively. Conclusions We established a one-pot one-step automated synthesis method using a CFN-MPS200 synthesizer that provided high radioactivity and stable radiochemical purity for possible clinical applications.

Objective 18F-labeled prostate-specific membrane antigen (PSMA) ligand, [18F]PSMA-1007, has the benefit of a higher synthetic yield and minimal excretion in the urine. High detection efficacy was reported in biochemical recurrence (BCR) of prostate cancer after radical prostatectomy. Thus, we evaluated the preliminary diagnostic utility of [18F]PSMA-1007 PET in patients with prostate cancer, focusing on the BCR which is not detected on conventional imaging. Methods We enrolled a total of 28 patients (age 51–79 years) with BCR of prostate cancer. BCR was defined as a continuous increase in PSA after radical prostatectomy or radiation therapy without any apparent recurrent lesions on conventional diagnostic imaging (CT and bone scintigraphy). PSMA-PET scanning was performed approximately 60 min after intravenous injection of [18F]PSMA-1007 (259 ± 37 MBq). PSMA-PET images were evaluated for lesion detection as well as its relation to PSA values and location. Results Abnormal uptake, which was suspected to be recurrence or metastasis, was detected in 92.9% (26/28) of patients with BCR. The SUVmax was 8.4 ± 6.4 in local recurrence, 11.5 ± 11.8 in pelvic lymph nodes (LN), and 4.1 ± 1.6 in bone metastasis. The detection rates were 66.7% in the PSA group-1 (0.1–0.5 ng/mL), 85.7% in the PSA group-2 (0.5–1.0 ng/mL), and 100% in the PSA group-3 (above 1.0 ng/mL). Among the PET-positive BCR patients (n = 26), local recurrence was detected in 57.7% (15/26), pelvic LN in 42.3% (11/26), and bone metastasis in 15.4% (4/26). In 53% (8/15) of BCR patients who were suspected of local recurrence, focal uptake was detected adjacent to the bladder on [18F]PSMA-1007 PET. This suggested the significant advantage of having minimal physiological urine excretion. Conclusions [18F]PSMA-1007 PET showed a high detection rate in recurrent and metastatic lesions. In patients with BCR, its high detection led to suitable treatment strategies, such as salvage radiation therapy or surgical removal of recurrent lymph nodes. Trial registration (UMIN Clinical Trials Registry) UMIN000037697.

Background An individual dosimetry system is essential for the evaluation of precise doses in nuclear medicine. The purpose of this study was to develop a system for calculating not only absorbed doses but also EQDX(α/β) from the PET-CT images of patients for targeted alpha therapy (TAT), considering the dose dependence of the relative biological effectiveness, the dose-rate effect, and the dose heterogeneity. Methods A general-purpose Monte Carlo particle transport code PHITS was employed as the dose calculation engine in the system, while the microdosimetric kinetic model was used for converting the absorbed dose to EQDX(α/β). PHITS input files for describing the geometry and source distribution of a patient are automatically created from PET-CT images, using newly developed modules of the radiotherapy package based on PHITS (RT-PHITS). We examined the performance of the system by calculating several organ doses using the PET-CT images of four healthy volunteers after injecting 18F-NKO-035. Results The deposition energy map obtained from our system seems to be a blurred image of the corresponding PET data because annihilation γ-rays deposit their energies rather far from the source location. The calculated organ doses agree with the corresponding data obtained from OLINDA 2.0 within 20%, indicating the reliability of our developed system. Test calculations by replacing the labeled radionuclide from 18F to 211At suggest that large dose heterogeneity in a target volume is expected in TAT, resulting in a significant decrease of EQDX(α/β) for higher-activity injection. Conclusions As an extension of RT-PHITS, an individual dosimetry system for nuclear medicine was developed based on PHITS coupled with the microdosimetric kinetic model. It enables us to predict the therapeutic and side effects of TAT based on the clinical data largely available from conventional external radiotherapy.

Prostate-specific membrane antigen (PSMA)-ligand PET/CT is performed on patients with prostate cancer to stage the disease initially or to identify sites of recurrence after definitive therapy. On the basis of clinical results, 18F-PSMA-1007 is a promising PSMA PET tracer, but detailed histologic confirmation has been lacking. Methods: Ninety-six patients with prostate cancer underwent 18F-PSMA-1007 PET/CT followed by either radical prostatectomy with lymphadenectomy or salvage lymphadenectomy. The histologic findings of PSMA PET-positive nodes were analyzed retrospectively. A lesion-based and patient-based analysis was performed comparing all positive lesions and only lesions larger than 3 mm on histopathology. Results: Of the patients, 90.6% received 18F-PSMA-1007 PET/CT for staging before the primary treatment, whereas 9.4% underwent imaging for biochemical recurrence. In 34.4% of the cohort, positive lymph nodes were present on imaging. In total, 1,746 lymph nodes were dissected in 96 patients. 18F-PSMA-1007 PET had a lesion-based sensitivity of 81.7%, a specificity of 99.6%, a positive predictive value of 92.4%, and a negative predictive value of 98.9% for detecting positive lymph nodes larger than 3 mm. In the analysis of all malignant nodes regardless of size, the overall sensitivity, specificity, positive predictive value, and negative predictive value on lesion-based analysis were 71.2%, 99.5%, 91.3%, and 97.9%, respectively. The patient-based analysis showed a sensitivity of 85.9% and a specificity of 99.5% for lymph nodes larger than 3 mm. Conclusion:18F-PSMA-1007 PET/CT reliably detects malignant lymph nodes and has an exceptional specificity of more than 99% for nodal metastases.

Background [18F]PSMA-1007, a positron emission tomography (PET) tracer, specifically targets prostate-specific membrane antigen (PSMA), which is highly expressed in prostate cancer. PSMA-PET is effective especially for regional detection of biochemical recurrence, which significantly affects patient management. Herein, we established and optimized a one-step radiolabeling protocol to separate and purify [18F]PSMA-1007 with a CFN-MPS200 synthesizer for clinical application. Results A dedicated single use cassette and synthesis program for [18F]PSMA-1007 was generated using a single-step method for direct precursor radiolabeling. In the cassette, three tube types (fluoro-elastomer, PharMed® BPT, silicone) and two different precursor salts (trifluoroacetic acid or acetic acid) were compared for optimization. Furthermore, three-lot tests were performed under optimized conditions for quality confirmation. Activity yields and mean radiochemical purity of [18F]PSMA-1007 were > 5000 MBq and 95%, respectively, at the end of synthesis, and the decay-corrected mean radiochemical yield from all three cassettes was approximately 40% using a trifluoroacetic acid salt precursor. Fluoro-elastomer tubings significantly increased the amount of non-radioactive PSMA-1007 (8.5 ± 3.1 μg/mL) compared to those with other tubings (0.3 μg/mL). This reduced the molar activity of [18F]PSMA-1007 synthesized in the cassette assembled by fluoro-elastomer tubings (46 GBq/μmol) compared to that with PharMed® BPT and silicone tubings (1184 and 1411 GBq/μmol, respectively). Residual tetrabutylammonium, acetonitrile, and dimethyl sulfoxide levels were Conclusions We successfully automated the production of [18F]PSMA-1007 for clinical use and optimized synthesis procedures with a CFN-MPS200 synthesizer using a silicone cassette and acetic acid salt precursor. Cassette availability will facilitate a wide spread use of [18F]PSMA-1007-PET, leading to an effective prostate cancer management.

Objective Boron neutron capture therapy (BNCT) is a noninvasive radiation therapy method for cancer treatment. In BNCT, 4-borono-2-[18F]-fluoro-L-phenylalanine (18F-FBPA) PET has been employed to estimate 10B accumulation in target tumors and normal tissues if 10B borono-L-phenylalanine (10B-BPA) is used as a boron carrier. The purpose of the current study was to evaluate the total distribution volume (Vt) of 18F-FBPA in normal organs of healthy volunteers by kinetic analysis and to estimate boron concentration in normal organs for the therapeutic dose of 10B-BPA using obtained Vt values. Methods Six healthy volunteers were injected with 18F-FBPA (3–5 MBq/kg), and 7 PET-CT scans were performed subsequently. 18F-FBPA radioactivity in whole blood and plasma was measured before, and eight times after the injection. PET images were analyzed by PMOD software. Twelve volumetric regions of interest including the brain, heart, right lung, spleen, liver, parotid salivary glands, esophagus, stomach, pancreas, intestines, and bone marrow were drawn manually for each subject and analyzed with the Logan plot and two Ichise multilinear analyses (MA1 and MA2). The better model was defined by several goodness-of-fit parameters and residual distribution. After Vt values had been derived, boron concentration was estimated in ppm for the 10B-BPA-fructose (10B-BPA-fr) dose 30 g 1 and 2 h post-injection using Vt and interpolated plasma activity data. Results The Ichise MA2 model showed the best fit among all models. Akaike Information Criterion (AIC) was the lowest for the Ichise’s MA2 in all regions (mean AIC value − 14.0) comparing to the other models (Logan plot mean AIC 31.4; Ichise MA1 model mean AIC − 4.2). Mean Vt values of the Ichise MA2 model ranged from 0.94 ± 0.14 ml/ml in the pancreas to 0.16 ± 0.02 ml/ml in the right lung. Estimated boron concentration for 10B-BPA-fr had the highest value in the pancreas (14.0 ± 1.9 ppm 1 h after, and 5.7 ± 1.7 ppm 2 h after the 18F-FBPA administration) and the lowest value in the right lung (2.4 ± 0.3 ppm 1 h, and 1.0 ± 0.3 ppm 2 h post-injection). Conclusion The 10B concentration in normal tissues was best estimated using Vt values of 18F-FBPA with the Ichise multilinear analysis 2 (MA2). Trail registry The UMIN clinical trial number: UMIN000022850.

4-Borono-2-[The produced [The mean amount of as-obtained [We developed a method for [

Tumor blood flow (TBF) is related to drug delivery and hypoxia, both of which can impact the efficacy of anti-cancer therapies. Although integrin αvβ3 expression is related to tumor angiogenesis, it remains unclear whether the degree of angiogenesis affects TBF. This study aimed to evaluate the expression of integrin αvβ3 in mouse tumor models using [68Ga]Ga-DOTA-c(RGDfK) peptide positron emission tomography (PET) and immunohistochemical staining. PET studies were conducted using mouse C6 glioma models and MIA PaCa-2 (n = 6 each). The [68Ga]Ga-DOTA-c(RGDfK) peptide was injected via the tail vein (2.17 ± 0.28 MBq), and 10 min static PET scans were performed. Immunohistochemical analysis was conducted using an integrin αVβ3 antibody. [68Ga]Ga-DOTA-c(RGDfK) peptide PET revealed higher uptake of the radiotracer in C6 gliomas than in MIA PaCa-2 tumors. The mean standardized uptake value was significantly higher in C6 gliomas (0.35 ± 0.058) than in MIA PaCa-2 tumors (0.17 ± 0.045). Histological analysis revealed intense integrin αVβ3 expression in the C6 gliomas, whereas the MIA PaCa-2 tumors had low expression levels. This study showed that the expression of integrin αvβ3 can be differentiated by the [68Ga]Ga-DOTA-c(RGDfK) peptide, suggesting the potential applicability of this peptide in the evaluation of the relationship between angiogenesis and TBF.

PET radioligands with low molar activity (MA) may underestimate the quantity of the target of interest because of competitive binding of the target with unlabeled ligand. The aim of this study was to evaluate the change in the whole-body distribution of 18F-PSMA-1007 targeting prostate-specific membrane antigen (PSMA) when solutions with different peptide concentrations are used. Methods: Mouse xenograft models of LNCaP (PSMA-positive prostate cancer) (n = 18) were prepared and divided into 3 groups according to the peptide concentration injected: a high-MA group (1,013 ± 146 GBq/μmol; n = 6), a medium-MA group (100.7 ± 23.1 GBq/μmol; n = 6), and a low-MA group (10.80 ± 2.84 GBq/μmol; n = 6). Static PET scans were performed 1 h after injection (scan duration, 10 min). SUVmean in tumor and normal organs was compared by the multiple-comparison test. Immunohistochemical staining and Western blot analysis were performed to confirm expression of PSMA in tumor, salivary gland, and kidney. Results: The low-MA group (SUVmean, 1.12 ± 0.30) showed significantly lower uptake of 18F-PSMA-1007 in tumor than did the high-MA group (1.97 ± 0.77) and the medium-MA group (1.81 ± 0.57). On the other hand, in salivary gland, both the low-MA group (SUVmean, 0.24 ± 0.04) and the medium-MA group (0.57 ± 0.08) showed significantly lower uptake than the high MA group (1.27 ± 0.28). The tumor-to-salivary gland SUVmean ratio was 1.73 ± 0.55 in the high-MA group, 3.16 ± 0.86 in the medium-MA group, and 4.78 ± 1.29 in the low-MA group. The immunohistochemical staining and Western blot analysis revealed significant overexpression of PSMA in tumor and low expression in salivary gland and kidney. Conclusion: A decrease in the MA level of the injected 18F-PSMA-1007 solution resulted in decreased uptake in tumor and, to a greater degree, in normal salivary gland. Thus, there is a possibility of minimizing the adverse effects in salivary gland by setting an appropriate MA level in PSMA-targeting therapy.

A 68-year-old man with sarcoidosis showed high 18F-FDG uptake in the mediastinal and hilar lymph nodes on 18F-FDG PET, suggesting active inflammation. 18F-fluoro-boronophenylalanine (FBPA) PET showed no significant uptake in the mediastinal and hilar lymph nodes, suggesting its cancer specificity as a substrate of l-type amino acid transporter 1. 18F-fluoro-boronophenylalanine PET can be used for precise evaluation in oncology when the differentiation between inflammation and metastasis is inconclusive on 18F-FDG PET.

Background [18F]PSMA-1007, a positron emission tomography (PET) tracer, specifically targets prostate-specific membrane antigen (PSMA), which is highly expressed in prostate cancer. PSMA-PET is effective especially for regional detection of biochemical recurrence, which significantly affects patient management. Herein, we established and optimized a one-step radiolabeling protocol to separate and purify [18F]PSMA-1007 with a CFN-MPS200 synthesizer for clinical application. Results A dedicated single use cassette and synthesis program for [18F]PSMA-1007 was generated using a single-step method for direct precursor radiolabeling. In the cassette, three tube types (fluoro-elastomer, PharMed® BPT, silicone) and two different precursor salts (trifluoroacetic acid or acetic acid) were compared for optimization. Furthermore, three-lot tests were performed under optimized conditions for quality confirmation. Activity yields and mean radiochemical purity of [18F]PSMA-1007 were > 5000 MBq and 95%, respectively, at the end of synthesis, and the decay-corrected mean radiochemical yield from all three cassettes was approximately 40% using a trifluoroacetic acid salt precursor. Fluoro-elastomer tubings significantly increased the amount of non-radioactive PSMA-1007 (8.5 ± 3.1 μg/mL) compared to those with other tubings (0.3 μg/mL). This reduced the molar activity of [18F]PSMA-1007 synthesized in the cassette assembled by fluoro-elastomer tubings (46 GBq/μmol) compared to that with PharMed® BPT and silicone tubings (1184 and 1411 GBq/μmol, respectively). Residual tetrabutylammonium, acetonitrile, and dimethyl sulfoxide levels were

Prostate-specific membrane antigen (PSMA)–ligand PET/CT is performed on patients with prostate cancer to stage the disease initially or to identify sites of recurrence after definitive therapy. On the basis of clinical results, 18F-PSMA-1007 is a promising PSMA PET tracer, but detailed histologic confirmation has been lacking. Methods: Ninety-six patients with prostate cancer underwent 18F-PSMA-1007 PET/CT followed by either radical prostatectomy with lymphadenectomy or salvage lymphadenectomy. The histologic findings of PSMA PET–positive nodes were analyzed retrospectively. A lesion-based and patient-based analysis was performed comparing all positive lesions and only lesions larger than 3 mm on histopathology. Results: Of the patients, 90.6% received 18F-PSMA-1007 PET/CT for staging before the primary treatment, whereas 9.4% underwent imaging for biochemical recurrence. In 34.4% of the cohort, positive lymph nodes were present on imaging. In total, 1,746 lymph nodes were dissected in 96 patients. 18F-PSMA-1007 PET had a lesion-based sensitivity of 81.7%, a specificity of 99.6%, a positive predictive value of 92.4%, and a negative predictive value of 98.9% for detecting positive lymph nodes larger than 3 mm. In the analysis of all malignant nodes regardless of size, the overall sensitivity, specificity, positive predictive value, and negative predictive value on lesion-based analysis were 71.2%, 99.5%, 91.3%, and 97.9%, respectively. The patient-based analysis showed a sensitivity of 85.9% and a specificity of 99.5% for lymph nodes larger than 3 mm. Conclusion: 18F-PSMA-1007 PET/CT reliably detects malignant lymph nodes and has an exceptional specificity of more than 99% for nodal metastases.

A previous study reported that a differential diagnosis between glioblastoma progression and radiation necrosis by 4-borono-2-[18F]-fluoro-phenylalanine ([18F]FBPA) PET can be made based on lesion-to-normal ratio of [18F]FBPA accumulation. Two-dimensional data acquisition mode PET alone system, with in-plane resolution of 7.9 mm and axial resolution of 13.9 mm, was used. In the current study, we aimed to confirm the differential diagnostic capability of [18F]FBPA PET/CT with higher PET spatial resolution by three-dimensional visual inspection and by measuring mean standardized uptake value (SUVmean), maximum SUV (SUVmax), metabolic tumor volume (MTV), and total lesion (TL) [18F]FBPA uptake. Twelve patients of glioma (9), malignant meningioma (1), hemangiopericytoma (1), and metastatic brain tumor (1) were enrolled. All had preceding radiotherapy. High-resolution three-dimensional data acquisition mode PET/CT with in-plane resolution of 4.07 mm and axial resolution of 5.41 mm was employed for imaging. Images were three-dimensionally analyzed using the PMOD software. SUVmean and SUVmax of lesion and normal brain were measured. Lesion MTV and TL FBPA uptake were calculated. The diagnostic accuracy of [18F]FBPA PET/CT in detecting recurrence (n = 6) or necrosis (n = 6) was verified by clinical follow-up. All parameters showed significantly higher values for tumor recurrence than for necrosis. SUVmean in recurrence was 2.95 ± 0.84 vs 1.18 ± 0.24 in necrosis (P = 0.014); SUVmax in recurrence was 4.63 ± 1.23 vs 1.93 ± 0.44 in necrosis (P = 0.014); MTV in recurrence was 44.92 ± 28.93 mL vs 10.66 ± 8.46 mL in necrosis (P = 0.032); and mean TL FBPA uptake in recurrence was 121.01 ± 50.48 g vs 12.36 ± 9.70 g in necrosis (P = 0.0029). In this preliminary feasibility study, we confirmed the possibility of differentiating tumor recurrence from radiation necrosis in patients with irradiated brain tumors by [18F]FBPA PET/CT using indices of SUVmean, SUVmax, MTV, and TL 18FBPA uptake.

Resting-state functional MRI (rs-fMRI) has revealed the existence of a default-mode network (DMN) based on spontaneous oscillations of the blood oxygenation level-dependent (BOLD) signal. The BOLD signal reflects the deoxyhemoglobin concentration, which depends on the relationship between the regional cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO2). However, these two factors cannot be separated in BOLD rs-fMRI. In this study, we attempted to estimate the functional correlations in the DMN by means of quantitative 15O-labeled gases and water PET, and to compare the contribution of the CBF and CMRO2 to the DMN. Nine healthy volunteers (5 men and 4 women; mean age, 47.0 ± 1.2 years) were studied by means of 15O-O2, 15O-CO gases and 15O-water PET. Quantitative CBF and CMRO2 images were generated by an autoradiographic method and transformed into MNI standardized brain template. Regions of interest were placed on normalized PET images according to the previous rs-fMRI study. For the functional correlation analysis, the intersubject Pearson’s correlation coefficients (r) were calculated for all pairs in the brain regions and correlation matrices were obtained for CBF and CMRO2, respectively. We defined r > 0.7 as a significant positive correlation and compared the correlation matrices of CBF and CMRO2. Significant positive correlations (r > 0.7) were observed in 24 pairs of brain regions for the CBF and 22 pairs of brain regions for the CMRO2. Among them, 12 overlapping networks were observed between CBF and CMRO2. Correlation analysis of CBF led to the detection of more brain networks as compared to that of CMRO2, indicating that the CBF can capture the state of the spontaneous activity with a higher sensitivity. We estimated the functional correlations in the DMN by means of quantitative PET using 15O-labeled gases and water. The correlation matrix derived from the CBF revealed a larger number of brain networks as compared to that derived from the CMRO2, indicating that contribution to the functional correlation in the DMN is higher in the blood flow more than the oxygen consumption.

Objective Boron neutron capture therapy (BNCT) is a noninvasive radiation therapy method for cancer treatment. In BNCT, 4-borono-2-[18F]-fluoro-L-phenylalanine (18F-FBPA) PET has been employed to estimate 10B accumulation in target tumors and normal tissues if 10B borono-L-phenylalanine (10B-BPA) is used as a boron carrier. The purpose of the current study was to evaluate the total distribution volume (Vt) of 18F-FBPA in normal organs of healthy volunteers by kinetic analysis and to estimate boron concentration in normal organs for the therapeutic dose of 10B-BPA using obtained Vt values. Methods Six healthy volunteers were injected with 18F-FBPA (3–5 MBq/kg), and 7 PET-CT scans were performed subsequently. 18F-FBPA radioactivity in whole blood and plasma was measured before, and eight times after the injection. PET images were analyzed by PMOD software. Twelve volumetric regions of interest including the brain, heart, right lung, spleen, liver, parotid salivary glands, esophagus, stomach, pancreas, intestines, and bone marrow were drawn manually for each subject and analyzed with the Logan plot and two Ichise multilinear analyses (MA1 and MA2). The better model was defined by several goodness-of-fit parameters and residual distribution. After Vt values had been derived, boron concentration was estimated in ppm for the 10B-BPA-fructose (10B-BPA-fr) dose 30 g 1 and 2 h post-injection using Vt and interpolated plasma activity data. Results The Ichise MA2 model showed the best fit among all models. Akaike Information Criterion (AIC) was the lowest for the Ichise’s MA2 in all regions (mean AIC value − 14.0) comparing to the other models (Logan plot mean AIC 31.4; Ichise MA1 model mean AIC − 4.2). Mean Vt values of the Ichise MA2 model ranged from 0.94 ± 0.14 ml/ml in the pancreas to 0.16 ± 0.02 ml/ml in the right lung. Estimated boron concentration for 10B-BPA-fr had the highest value in the pancreas (14.0 ± 1.9 ppm 1 h after, and 5.7 ± 1.7 ppm 2 h after the 18F-FBPA administration) and the lowest value in the right lung (2.4 ± 0.3 ppm 1 h, and 1.0 ± 0.3 ppm 2 h post-injection). Conclusion The 10B concentration in normal tissues was best estimated using Vt values of 18F-FBPA with the Ichise multilinear analysis 2 (MA2). Trail registry The UMIN clinical trial number: UMIN000022850. Electronic supplementary material The online version of this article (10.1007/s12149-019-01427-9) contains supplementary material, which is available to authorized users.

L-type amino acid transporter 1 (LAT1) is strongly expressed on the cell membrane in various types of human cancer cells, while being minimally expressed in normal or inflammatory tissues. Therefore, LAT1-targeting PET tracers have been developed for cancer-specific imaging. The purpose of this study was to study the distribution of two LAT1-targeting PET tracers, L-4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) and L-3-18F-alpha-methyl tyrosine (18F-FAMT), in relation to the tumor blood flow, using rat xenograft models. Rat tumor xenograft models of C6 glioma (n = 4; tumors = 8) and MIA PaCa-2 (pancreatic cancer) (n = 4; tumors = 6) were used. The expressions of LAT1 and CD98hc were evaluated by both immunofluorescence staining and western blot analysis. Dynamic PET was performed after injection of 18F-FAMT or 18F-FBPA (scan duration = 70 min) following 15O-water PET (scan duration = 10 min). The PET data were subjected to kinetic analyses, and the K1, k2, and total distribution volume (Vt) were calculated using the one-tissue compartment model. The accumulation of the LAT1 tracers was expressed in terms of their Vt. Tumor blood flow (TBF) was represented by the K1 value in 15O-water PET. LAT1/CD98hc expression was confirmed in both xenografts by immunofluorescence staining. Western blot analysis showed higher functional expression of LAT1 in the C6 glioma cells as compared to the MIA PaCa-2 cells (C6 glioma/MIA PaCa-2 relative expression ratio = 1.70). The Vt values of both 18F-FBPA and 18F-FAMT were significantly higher in the C6 glioma xenografts than in the MIA PaCa-2 xenografts (C6 glioma: 2.27 ± 0.35 and 2.03 ± 0.23, respectively; MIA PaCa-2: 1.28 ± 0.26 and 1.35 ± 0.15, respectively). Meanwhile, there was no significant correlation of the Vt value of either 18F-FBPA or 18F-FAMT with the TBF, in either the C6 glioma or the MIA PaCa-2 xenografts. This study revealed that total distribution volumes of the LAT1-targeting PET tracers 18F-FBPA and 18F-FAMT were independent of the tumor blood flow and might reflect the functional expression levels of LAT1 in the C6 glioma and MIA PaCa-2 xenograft models.

In boron neutron capture therapy (BNCT) for cancer, the accurate estimation of 10B tissue concentrations, especially in neighboring normal organs, is important to avoid adverse effects. The 10B concentration in normal organs after loading with 10B, however, has not been established in humans. In this study, we performed 4-borono-2-[18F]-fluoro-phenylalanine (18FBPA) PET in healthy volunteers and estimated the chronological changes in the 10B concentrations of normal organs. In 6 healthy volunteers, whole-body 18FBPA PET scans were repeated 7 times during 1 h, and the mean 18FBPA distributions of 13 organs were measured. Based on the 18FBPA PET data, we then estimated the changes in the 10B concentrations of the organs when the injection of a therapeutic dose of 10BPA–fructose complex (10BPA–fr; 30 g, 500 mg/kg body weight) was assumed. The maximum mean 18FBPA concentrations were reached at 2–6 min after injection in all the organs except the brain and urinary bladder. The mean 18FBPA concentration in normal brain plateaued at 24 min after injection. When the injection of a therapeutic dose of 10BPA–fr was assumed, the estimated mean 10B concentration in the kidney increased to 126.1 ± 24.2 ppm at 3 min after injection and then rapidly decreased to 30.9 ± 7.4 ppm at 53 min. The estimated mean 10B concentration in the bladder gradually increased and reached 383.6 ± 214.7 ppm at 51 min. The mean 10B concentration in the brain was estimated to be 7.6 ± 1.5 ppm at 57 min. 18FBPA PET has a potential to estimate 10B concentration of normal organs before neutron irradiation of BNCT when several assumptions are validated in the future studies.

Purpose The purpose of this study was to evaluate the usefulness of L-4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) as a tumor-specific probe, in comparison to 18F-FDG and 11C-methionine (Met), focusing on its transport selectivity by L-type amino acid transporter 1 (LAT1), which is highly upregulated in cancers.

A previous study reported that a differential diagnosis between glioblastoma progression and radiation necrosis by 4-borono-2-[Twelve patients of glioma (9), malignant meningioma (1), hemangiopericytoma (1), and metastatic brain tumor (1) were enrolled. All had preceding radiotherapy. High-resolution three-dimensional data acquisition mode PET/CT with in-plane resolution of 4.07 mm and axial resolution of 5.41 mm was employed for imaging. Images were three-dimensionally analyzed using the PMOD software. SUVmean and SUVmax of lesion and normal brain were measured. Lesion MTV and TL FBPA uptake were calculated. The diagnostic accuracy of [All parameters showed significantly higher values for tumor recurrence than for necrosis. SUVmean in recurrence was 2.95 ± 0.84 vs 1.18 ± 0.24 in necrosis (P = 0.014); SUVmax in recurrence was 4.63 ± 1.23 vs 1.93 ± 0.44 in necrosis (P = 0.014); MTV in recurrence was 44.92 ± 28.93 mL vs 10.66 ± 8.46 mL in necrosis (P = 0.032); and mean TL FBPA uptake in recurrence was 121.01 ± 50.48 g vs 12.36 ± 9.70 g in necrosis (P = 0.0029).In this preliminary feasibility study, we confirmed the possibility of differentiating tumor recurrence from radiation necrosis in patients with irradiated brain tumors by [

Objective Resting-state functional MRI (rs-fMRI) has revealed the existence of a default-mode network (DMN) based on spontaneous oscillations of the blood oxygenation level-dependent (BOLD) signal. The BOLD signal reflects the deoxyhemoglobin concentration, which depends on the relationship between the regional cerebral blood flow (CBF) and the cerebral metabolic rate of oxygen (CMRO2). However, these two factors cannot be separated in BOLD rs-fMRI. In this study, we attempted to estimate the functional correlations in the DMN by means of quantitative 15O-labeled gases and water PET, and to compare the contribution of the CBF and CMRO2 to the DMN. Methods Nine healthy volunteers (5 men and 4 women; mean age, 47.0 ± 1.2 years) were studied by means of 15O-O2, 15O-CO gases and 15O-water PET. Quantitative CBF and CMRO2 images were generated by an autoradiographic method and transformed into MNI standardized brain template. Regions of interest were placed on normalized PET images according to the previous rs-fMRI study. For the functional correlation analysis, the intersubject Pearson’s correlation coefficients (r) were calculated for all pairs in the brain regions and correlation matrices were obtained for CBF and CMRO2, respectively. We defined r > 0.7 as a significant positive correlation and compared the correlation matrices of CBF and CMRO2. Results Significant positive correlations (r > 0.7) were observed in 24 pairs of brain regions for the CBF and 22 pairs of brain regions for the CMRO2. Among them, 12 overlapping networks were observed between CBF and CMRO2. Correlation analysis of CBF led to the detection of more brain networks as compared to that of CMRO2, indicating that the CBF can capture the state of the spontaneous activity with a higher sensitivity. Conclusions We estimated the functional correlations in the DMN by means of quantitative PET using 15O-labeled gases and water. The correlation matrix derived from the CBF revealed a larger number of brain networks as compared to that derived from the CMRO2, indicating that contribution to the functional correlation in the DMN is higher in the blood flow more than the oxygen consumption.

Background Positron emission tomography (PET) studies using 15O-labeled CO2, O2, and CO have been used in humans to evaluate cerebral blood flow (CBF), the cerebral oxygen extraction fraction (OEF), and the cerebral metabolic rate of oxygen (CMRO2) and cerebral blood volume (CBV), respectively. In preclinical studies, however, PET studies using 15O-labeled gases are not widely performed because of the technical difficulties associated with handling labeled gases with a short half-life. The aims of the present study were to evaluate the scatter fraction using 3D-mode micro-PET for 15O-labeled gas studies and the influence of reconstruction algorithms on quantitative values. Nine male SD rats were studied using the steady state inhalation method for 15O-labeled gases with arterial blood sampling. The resulting PET images were reconstructed using filtered back projection (FBP), ordered-subset expectation maximization (OSEM) 2D, or OSEM 3D followed by maximum a posteriori (OSEM3D-MAP). The quantitative values for each brain region and each reconstruction method were calculated by applying different reconstruction methods. Results The quantitative values for the whole brain as calculated using FBP were 46.6 ± 12.5 mL/100 mL/min (CBF), 63.7 ± 7.2% (OEF), 5.72 ± 0.34 mL/100 mL/min (CMRO2), and 5.66 ± 0.34 mL/100 mL (CBV), respectively. The CBF and CMRO2 values were significantly higher when the OSEM2D and OSEM3D-MAP reconstruction methods were used, compared with FBP, whereas the OEF values were significantly lower when reconstructed using OSEM3D-MAP. Conclusions We evaluated the difference in quantitative values among the reconstruction algorithms using 3D-mode micro-PET. The iterative reconstruction method resulted in significantly higher quantitative values for CBF and CMRO2, compared with the values calculated using the FBP reconstruction method. Electronic supplementary material The online version of this article (10.1186/s13550-017-0335-7) contains supplementary material, which is available to authorized users.

Purpose The purpose of this study was to establish a practical method to estimate the absolute boron concentrations in the tissues based on the standardized uptake values (SUVs) after administration of 4-borono-phenylalanine (BPA) using 4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) PET. Methods Rat xenograft models of C6 glioma (n = 7, body weight 241 ± 28.0 g) were used for the study. PET was performed 60 min after intravenous injection of 18F-FBPA (30.5 ± 0.7 MBq). After the PET scanning, BPA-fructose (167.3 ± 18.65 mg/kg) was administered by slow intravenous injection to the same subjects. The rats were killed 60 min after the BPA injection and tissue samples were collected from the major organs and tumors. The absolute boron concentrations (unit: ppm) in the samples were measured by inductively coupled plasma optical emission spectrometry (ICP-OES). The boron concentrations in the tissues/tumors were also estimated from the 18F-FBPA PET images using the following formula: estimated absolute boron concentration (ppm) = 0.0478 × [BPA dose (mg/kg)] × SUV. The measured absolute boron concentrations (mBC) by ICP-OES and the estimated boron concentrations (eBC) from the PET images were compared. Results The percent difference between the mBC and eBC calculated based on the SUVmax was −5.2 ± 21.1% for the blood, −9.4 ± 22.3% for the brain, 1.6 ± 21.3% for the liver, −14.3 ± 16.8% for the spleen, −9.5 ± 27.5% for the pancreas, and 3.4 ± 43.2% for the tumor. Relatively large underestimation was observed for the lung (−48.4 ± 16.2%), small intestine (−37.8 ± 19.3%) and large intestine (−33.9 ± 11.0%), due to the partial volume effect arising from the air or feces contained in these organs. In contrast, relatively large overestimation was observed for the kidney (34.3 ± 29.3%), due to the influence of the high uptake in urine. Conclusions The absolute boron concentrations in tissues/tumors can be estimated from the SUVs on 18F-FBPA PET using a practical formula. Caution must be exercised in interpreting the estimated boron concentrations in the lung, small intestine and large intestine, to prevent the adverse effects of overexposure, which could occur due to underestimation by partial volume effect using PET. Electronic supplementary material The online version of this article (doi:10.1007/s12149-017-1172-5) contains supplementary material, which is available to authorized users.

Schema of the tube connection for the 15O-gas supply. Figure S2. Workflow for image reconstruction and data analysis. Figure S3. Relationship between the radioactivity of 15O-gas flow and the radioactivity concentration in the lung. Figure S4. Percent change in the radioactivity concentration against FBP (**Pâ

Background In boron neutron capture therapy (BNCT), positron emission tomography (PET) with 4-borono-2-18F-fluoro-phenylalanine (FBPA) is the only method to estimate an accumulation of 10B to target tumor and surrounding normal tissue after administering 10B carrier of L-paraboronophenylalanine and to search the indication of BNCT for individual patient. Absolute concentration of 10B in tumor has been estimated by multiplying 10B concentration in blood during BNCT by tumor to blood radioactivity (T/B) ratio derived from FBPA PET. However, the method to measure blood radioactivity either by blood sampling or image data has not been standardized. We compared image-derived blood radioactivity of FBPA with blood sampling data and studied appropriate timing and location for measuring image-derived blood counts. Methods We obtained 7 repeated whole-body PET scans in five healthy subjects. Arterialized venous blood samples were obtained from the antecubital vein, heated in a heating blanket. Time-activity curves (TACs) of image-derived blood radioactivity were obtained using volumes of interest (VOIs) over ascending aorta, aortic arch, pulmonary artery, left and right ventricles, inferior vena cava, and abdominal aorta. Image-derived blood radioactivity was compared with those measured by blood sampling data in each location. Results Both the TACs of blood sampling radioactivity in each subject, and the TACs of image-derived blood radioactivity showed a peak within 5 min after the tracer injection, and promptly decreased soon thereafter. Linear relationship was found between blood sampling radioactivity and image-derived blood radioactivity in all the VOIs at any timing of data sampling (p

In boron neutron capture therapy (BNCT) for cancer, the accurate estimation ofIn 6 healthy volunteers, whole-bodyThe maximum mean

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) represents an attractive target for tumor diagnosis agents. Previously, the radioiodinated 4-(3-iodoanilino)-6,7-diethoxyquinazoline ([(125)I]m-IPQ) has been reported to possess good characteristics as a tumor imaging agent; however, it was also found to have low in vivo stability. To improve the in vivo stability, m-IPQ derivatives, 4-(3-iodophenoxy)-6,7-diethoxyquinazoline (PHY) and 4-(3-iodobenzylamino)-6,7-diethoxyquinazoline (BAY) were designed and synthesized, and the biological studies of [(125)I]PHY and [(125)I]BAY were performed to evaluate these new ligands as in vivo tumor diagnosis agents.PHY and BAY were synthesized according to previous reports. The EGFR-TK inhibitory potency of these new compounds was measured and compared to other EGFR-TK inhibitors. Radiolabeled [(125)I]PHY and [(125)I]BAY were synthesized by an iododestannylation reaction. Biodistribution studies of these radioligands were conducted in normal mice and tumor-bearing mice. Furthermore, selectivity and binding characteristics of [(125)I]PHY were analyzed by in vitro blocking studies and a binding assay.The new derivatives were found to have high inhibitory potency against EGFR-TK (PHY: IC50 = 12.7 ± 7.2 nM, BAY: IC50 = 51.0 ± 8.9 nM). [(125)I]PHY and [(125)I]BAY were conveniently synthesized from tributylstannyl precursors. In in vivo biodistribution studies, [(125)I]PHY and [(125)I]BAY were observed to have lower uptake in the stomach, an indication of deiodination, than [(125)I]m-IPQ. Moreover, [(125)I]PHY showed high uptake and prolonged retention in tumors and low accumulation in blood and muscle tissue resulting in a good tumor-to-blood ratio (0.94-1.50) and tumor-to-muscle ratio (1.02-1.95). The EGFR-TK selectivity of [(125)I]PHY was confirmed by pretreatment experiments with specific EGFR-TK inhibitors.New radioiodinated quinazoline derivatives were synthesized, which were found to have improved in vivo stability. In particular, [(125)I]PHY showed higher tumor accumulation than the other ligands which was indicative of selective binding to EGFR-TK. These desirable characteristics for [(125)I]PHY suggest that the (123)I-labeled counterpart, [(123)I]PHY, could be a possible candidate for cancer diagnosis radiopharmaceutical.

A radioiodinated analog of PD153035 (m-IPQ) was evaluated as a potential epidermal growth factor receptor tyrosine kinase (EGFR-TK) activity imaging ligand for SPECT. The 50% inhibition concentration (IC50) value of m-IPQ for EGFR-TK phosphorylation inhibition was evaluated and compared to various EGFR-TK inhibitors. [125I]m-IPQ was synthesized by iododestannylation reaction. Biodistribution study of [125I]m-IPQ was conducted in normal mice and tumor-bearing mice. The selectivity and binding characteristics (B max and K d) were analyzed. The quinazoline derivative m-IPQ was found to have high inhibitory potency (IC50: 50.5 ± 3.5 nM) and selectivity toward EGFR-TK. In vivo biodistribution studies of [125I]m-IPQ demonstrated its rapid clearance and low retention in normal tissue. On the other hand, high tumor uptake was observed. However, the increase in [125I]m-IPQ uptake in the stomach as a deiodination parameter was found. Thus, [125I]m-IPQ showed low in vivo stability. The selectivity toward EGFR-TK of m-IPQ was confirmed by the pretreatment experiment with EGFR-TK specific inhibitors, PD153035, Genistein. [125I]m-IPQ bound to single population of binding sites with high affinity and kinetic parameter. In addition, [125I]m-IPQ was bound to EGFR-TK according to the amount of EGFR-TK expression in the tumor. [125I]m-IPQ showed a relatively high tumor accumulation with selective EGFR-TK binding. Moreover, the tumor uptake of [125I]m-IPQ might be reflected in the amount of EGFR-TK expression in the tumor. These good characteristics of [125I]m-IPQ suggested that a 123I-labeled counterpart, [123I]m-IPQ, would have great potential for EGFR-TK imaging with SPECT. However, the in vivo stability of this compound needs to improve.