In vivo-stable bis-iminobiotin for targeted radionuclide delivery with the mutant streptavidin.

Targeted delivery of radionuclides to tumors is significant in theranostics applications for precision medicine. Pre-targeting, in which a tumor-targeting vehicle and a radionuclide-loaded effector small molecule are administered separately, holds promise since it can reduce unnecessary internal radiation exposure of healthy cells and can minimize radiation decay. The success of the pre-targeting delivery requires an in vivo-stable tumor-targeting vehicle selectively binding to tumor antigens and an in vivo-stable small molecule effector selectively binding to the vehicle accumulated on the tumor. We previously reported a drug delivery system composed of a low-immunogenic streptavidin with weakened affinity to endogenous biotin and a bis-iminobiotin with high affinity to the engineered streptavidin. It was, however, unknown whether the bis-iminobiotin is stable in vivo when administered alone for the pre-targeting applications. Here we report a new in vivo-stable bis-iminobiotin derivative. The keys to success were the identification of the degradation site of the original bis-iminobiotin treated with mouse plasma and the structural modification of the degradation site. We disclosed the successful pre-targeting delivery of astatine-211 (211At), α-particle emitter, to the CEACAM5-positive tumor in xenograft mouse models.

Simultaneous assessment of left ventricular mechanical dyssynchrony using integrated 13N-ammonia PETMR system: direct comparison of PET phase analysis and MR feature tracking.

BACKGROUND: To compare phase analysis with positron emission tomography (PA) and magnetic resonance feature tracking derived myocardial strain (FT) for left ventricular (LV) mechanical dyssynchrony using PETMR system in patients with ischemic heart disease. METHODS AND RESULTS: Patients who underwent rest-pharmacological stress 13N ammonia PETMR were enrolled. Histogram bandwidth (BW) and phase standard deviation (PSD) were compared to global longitudinal, long axis radial, short axis circumferential, and radial strain (GLS, GRS, SA Circ, and SA Rad) obtained from FT. LV dyssynchrony index (SDI) derived from PA and FT were compared. BW and PSD showed significant correlations with FT (a Pearson's coefficient r = 0.64, P < .0001, and r = 0.51, P < .0001 for SA Circ; r = 0.67, P < .0001, and r = 0.74, P < .0001 for GLS; r = - 0.60, P < .0001, r = - 0.61, P < .0001 for SA Rad; r = - 0.62, P < .0001, and r = - 0.68, P < .0001 for GRS, respectively). Bland-Altman plots for SDI showed a preferable agreement (95% limit of agreement - 0.12 to 0.075, - 0.20 to 0.098, - 0.38 to 0.077, and - 0.37 to 0.032; bias 0.0068 ± 0.056, 0.026 ± 0.068, 0.11 ± 0.088, and 0.13 ± 0.079 for SA Circ, SA Rad, GLS, and GRS, respectively). CONCLUSION: In simultaneous acquisition using PETMR, comparison of PET phase analysis and MR strain showed a good correlation.

Preliminary Evaluation of Astatine-211-Labeled Bombesin Derivatives for Targeted Alpha Therapy.

There are various diagnostic and therapeutic agents for prostate cancer using bombesin (BBN) derivatives, but astatine-211 (211At)-labeled BBN derivatives have yet to be studied. This study presented a preliminary evaluation of 211At-labeled BBN derivative. Several nonradioactive iodine-introduced BBN derivatives (IB-BBNs) with different linkers were synthesized and their binding affinities measured. Because IB-3 exhibited a comparable affinity to native BBN, [211At]AB-3 was synthesized and the radiochemical yields of [211At]AB-3 was 28.2 ± 2.4%, with a radiochemical purity of >90%. The stability studies and cell internalization/externalization experiments were performed. [211At]AB-3 was taken up by cells and internalized; however, radioactivity effluxed from cells over time. In addition, the biodistribution of [211At]AB-3, with and without excess amounts of BBN, were evaluated in PC-3 tumor-bearing mice. Despite poor stability in murine plasma, [211At]AB-3 accumulated in tumor tissue (4.05 ± 0.73%ID/g) in PC-3 tumor-bearing mice, which was inhibited by excess native BBN (2.56 ± 0.24%ID/g). Accumulated radioactivity in various organs is probably due to free 211At. Peptide degradation in murine plasma and radioactivity efflux from cells are areas of improvement. The development of 211At-labeled BBN derivatives requires modifying the BBN sequence and preventing deastatination.

Detectability of Malignant Lesions by Whole-Body Magnetic Resonance Imaging Using Whole-Body Integrated Positron Emission Tomography/Magnetic Resonance Imaging.

PURPOSE: To assess the diagnostic ability of whole-body magnetic resonance imaging (MRI) using integrated positron emission tomography/MRI(PET/MRI). METHODS: Axial T2-weighted image (T2WI), diffusion-weighted imaging (DWI), coronal T1-weighted image (T1WI), axial volumetric interpolated breath-hold examination in the lung field, and 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG-PET) were evaluated in combination with T2WI alone, T2WI + DWI, T2WI + DWI + T1WI, T2WI + DWI + T1WI + volumetric interpolated breath-hold examination (all MRI images), and all MRI + FDG-PET. RESULTS: A total of 370 lesions were observed in 90 (62.5%) of the 144 patients. The lesion-based sensitivities were 62%, 74%, 74%, 76%, and 94%, and the patient-based sensitivities were 70%, 77%, 77%, 77%, and 81% using T2WI, T2WI + DWI, T2WI + DWI + T1WI, all MRI, and all MRI + FDG-PET, respectively. There were significant differences in the lesion-based sensitivity between T2WI and other sequence combinations and between all MRI and all MRI + FDG-PET. No significant differences were observed between any combinations among the patient-based sensitivities. CONCLUSION: The sensitivity of whole-body MRI was lower when lesion based, but almost equivalent when patient based compared with PET/MRI.

Characterization of the role of sphingomyelin synthase 2 in glucose metabolism in whole-body and peripheral tissues in mice.

Sphingomyelin synthase 2 (SMS2) is a proposed potential therapeutic target for obesity and insulin resistance. However, the contributions of SMS2 to glucose metabolism in tissues and its possible therapeutic mechanisms remain unclear. Thus, to determine whole-body glucose utilization and the contributions of each insulin-targeted tissue to glucose uptake, we performed a glucose kinetics study, using the radiolabeled glucose analog (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG), in wild-type (WT) and SMS2 knockout (KO) mice. Insulin signaling was enhanced in the liver, white adipose tissue and skeletal muscle of SMS2 KO mice compared with those of WT mice. In addition, compared with in WT mice, blood clearance of (18)F-FDG was accelerated in SMS2 KO mice when they were fed either a normal or a high fat diet. (18)F-FDG uptake was also increased in insulin-targeted tissues such as skeletal muscle in the SMS2 KO mice. Whereas skeletal muscle sphingolipid content was not clearly affected, plasma levels of very long-chain fatty acid (VLCFA)-containing ceramides were markedly increased in SMS2 KO mice, compared with in WT mice. We also generated liver-conditional SMS2 KO mice and performed glucose and insulin tolerance tests on mice with a high fat diet. However, no significant effect was observed. Thus, our study provided evidence that genetic inhibition of SMS2 elevated glucose clearance through activation of glucose uptake into insulin-targeted tissues such as skeletal muscle by a mechanism independent of hepatic SMS2. Our findings further indicate that this occurs, at least in part, via indirect mechanisms such as elevation of VLCFA-containing ceramides.

Irbesartan attenuates atherosclerosis in Watanabe heritable hyperlipidemic rabbits: noninvasive imaging of inflammation by 18F-fluorodeoxyglucose positron emission tomography.

The purpose of this study was to assess the usefulness of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in evaluating the antiatherogenic effects of irbesartan, an angiotensin II type 1 receptor blocker. Watanabe heritable hyperlipidemic rabbits were divided into the irbesartan-treated group (75 mg/kg/d; n  =  14) and the control group (n  =  14). After a 9-month treatment, rabbits underwent 18F-FDG PET. Using the aortic lesions, autoradiography and histologic examinations were performed. PET imaging clearly visualized the thoracic lesions of control rabbits and showed a significant decrease in the 18F-FDG uptake level of irbesartan-treated rabbits (78.8% of controls; p < .05). Irbesartan treatment significantly reduced the plaque size (43.1% of controls) and intraplaque macrophage infiltration level (48.1% of controls). The 18F-FDG uptake level in plaques positively correlated with the plaque size (r  =  .65, p < .05) and macrophage infiltration level (r  =  .57, p < .05). Noninvasive imaging by 18F-FDG PET is useful for evaluating the therapeutic effects of irbesartan and reflects inflammation, a key factor involved in the therapeutic effects.

Differential centiloid scale normalization techniques: comparison between hybrid PET/MRI and independently acquired MRI.

OBJECTIVE: Centiloid (CL) scales play an important role in semiquantitative analyses of amyloid-ß (Aß) PET. CLs are derived from the standardized uptake value ratio (SUVR), which needs Aß positron emission tomography (PET) normalization processing. There are two methods to collect the T1-weighted imaging (T1WI) for normalization: (i) anatomical standardization using simultaneously acquired T1WI (PET/MRI), usually adapted to PET images from PET/MRI scanners, and (ii) T1WI from a separate examination (PET + MRI), usually adapted to PET images from PET/CT scanners. This study aimed to elucidate the correlations and differences in CLs between when using the above two T1WI collection methods. METHODS: Among patients who underwent Aß PET/MRI (using 11C-Pittuberg compound B (11C-PiB) or 18F-flutemetamol (18F-FMM)) at our institution from 2015 to 2023, we selected 49 patients who also underwent other additional MRI examinations, including T1WI for anatomic standardization within 3 years. Thirty-one of them underwent 11C-PiB PET/MRI, and 18 participants underwent 18F-FMM PET/MRI. Twenty-five of them, additional MRI acquisition parameters were identical to simultaneous MRI during PET, and 24 participants were different. After normalization using PET/MRI or PET + MRI method each, SUVR was measured using the Global Alzheimer's Association Initiative Network cerebral cortical and striatum Volume of Interest templates (VOI) and whole cerebellum VOI. Subsequently, CLs were calculated using the previously established equations for each Aß PET tracer. RESULTS: Between PET/MRI and PET + MRI methods, CLs correlated linearly in 11C-PiB PET (y = 1.00x - 0.11, R2 = 0.999), 18F-FMM PET (y = 0.97x - 0.12, 0.997), identical additional MRI acquisition (y = 1.00x + 0.33, 0.999), different acquisition (y = 0.98x - 0.43, 0.997), and entire study group (y = 1.00x - 0.24, 0.999). Wilcoxon signed-rank test revealed no significant differences: 11C-PiB (p = 0.49), 18F-FMM (0.08), and whole PET (0.46). However, significant differences were identified in identical acquisition (p = 0.04) and different acquisition (p = 0.02). Bland-Altman analysis documented only a small bias between PET/MRI and PET + MRI in 11C-PiB PET, 18F-FMM PET, identical additional MRI acquisition, different acquisition, and whole PET (- 0.05, 0.67, - 0.30, 0.78, and 0.21, respectively). CONCLUSIONS: Anatomical standardizations using PET/MRI and using PET + MRI can lead to almost equivalent CL. The CL values obtained using PET/MRI or PET + MRI normalization methods are consistent and comparable in clinical studies.

Activation cross sections of proton-induced reactions on natural platinum up to 30 MeV.

Activation cross sections of proton-induced reactions on natural platinum were measured. The stacked-foil activation technique and high-resolution gamma-ray spectrometry were used. The production cross sections of 198, 196, 196m2, 195, 194, 193, 192, 191Au, 191Pt, and 192, 190Ir were determined up to 30 MeV. The experimental results were compared with previous experimental data and theoretical calculations in the TENDL-2019 library.

[The Questionnaire Survey of Japanese Practice and Environment for Targeted Radionuclide Therapy in 2021].

PURPOSE: Recently, the targeted radionuclide therapy (TRT) was urgently required to adapt the practice and environment because of the implementation of novel therapeutic radiopharmaceuticals such as alpha- and beta- radionuclides therapy. The present study aimed to clarify the questionnaire survey with the current situation (safety controls for workers and patients) at Japanese TRT facilities. METHODS: The massive questionnaire survey, 2 months from October to November 2021, was conducted among nationwide 251 facilities that have performed TRT in the past two years. The alpha- and beta- therapeutic radiopharmaceuticals were categorized and answered by one representative of the facility under anonymity. We analyzed the actual situation of each facility related to occupational exposure, radiation protection, contamination inspection, patient release criteria, and dosimetry for TRT. RESULTS: The survey response rate was 69.1% (174 facilities). About 75% of these facilities reported that they either follow the guidelines or take their own measures to reduce occupational exposure. The confirmed means of patient release criteria were 68.0% with the administered radioactivity and 87.2% with the ambient dose rate. The cold run was not performed for the first time at 15.0% and 10.0% of the facilities for ß- and α-emitting radionuclides, respectively. The facilities without attachment syringe shields were 39.2% for alpha-radionuclides therapy and 20.3% for beta-radionuclides therapy. CONCLUSION: We clarified the Japanese problem for TRT practice and environment by the questionnaire survey. Our findings indicated that the Japanese guidelines and manuals for TRT were not partly followed in the nationwide facilities.

Oxygen extraction fraction is not uniform in human brain: a positron emission tomography study.

The regional differences in cerebral oxygen extraction fraction (OEF) in brain were investigated using positron emission tomography (PET) in detail with consideration of systemic errors in PET measurement estimated by simulation studies. The cerebral blood flow (CBF), cerebral blood volume (CBV), OEF, and cerebral metabolic rate of oxygen (CMRO2) were measured on healthy men by PET with 15O-labeled gases. The OEF values in the pons and the parahippocampal gyrus were significantly smaller than in the other brain regions. The OEF value in the lateral side of the occipital cortex was largest among the cerebral cortical regions. Simulation studies have revealed that errors in OEF caused by regional differences in the distribution volume of 15O-labeled water, as well as errors in OEF caused by a mixture of gray and white matter, must be negligible. The regional differences in OEF in brain must exist which might be related to physiological meanings.Article title: Kindly check and confirm the edit made in the article title.I have checked the article title and it is OK as is. Trial registration: The UMIN clinical trial number: UMIN000033382, https://www.umin.ac.jp/ctr/index.htm.

Manual on the proper use of meta-[211At] astato-benzylguanidine ([211At] MABG) injections in clinical trials for targeted alpha therapy (1st edition).

In this manuscript, we present the guideline for use of meta-[211At] astatobenzylguanidine ([211At] MABG), a newly introduced alpha emitting radiopharmaceutical to the up-coming World's first clinical trial for targeted alpha therapy (TAT) at Fukushima Medical University in Japan, focusing on radiation safety issues in Japan. This guideline was prepared based on a study supported by the Ministry of Health, Labour, and Welfare, and approved by the Japanese Society of Nuclear Medicine on Oct. 5th, 2021. The study showed that patients receiving [211At] MABG do not need to be admitted to a radiotherapy room and that TAT using [211At] MABG is possible on an outpatient basis. The radiation exposure from the patient is within the safety standards of the ICRP and IAEA recommendations for the general public and caregivers or patient's family members. In this guideline, the following contents are also included: precautions for patients and their families, safety management associated with the use of [211At] MABG, education and training, and disposal of medical radioactive contaminants. TAT using [211At] MABG in Japan should be carried out according to this guideline. Although this guideline is based on the medical environment and laws and regulations in Japan, the issues for radiation protection and evaluation methodology presented in this guideline are useful and internationally acceptable as well.

Production cross sections of samarium-153 and -145 via alpha-particle-induced reactions on natural neodymium.

Production cross sections of 153,145Sm via alpha-particle-induced reactions on natNd were measured up to 23 MeV. The stacked-foil activation technique and high-resolution gamma-ray spectrometry were adopted for the measurement. The obtained cross sections were compared with the literature data and the TENDL-2019 and TENDL-2021 values. Physical thick target yields of the two radionuclides were derived from the measured cross sections.

Evaluation of a model-based attenuation correction method on whole-body 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging.

The bone cannot be evaluated using magnetic resonance attenuation correction (MRAC) with the Dixon sequence. To solve this issue, the present study aimed to evaluate model-based AC for whole-body 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) by creating bone segmentation. We analyzed and evaluated the data of 31 consecutive patients. The Biograph mMR (Siemens Healthcare) was used for clinical whole-body 18F-FDG PET/MRI with the conventional MRAC method, and OSIRIX MD software was used to analyze the images. After the examination, the new model-based post-processing MRAC was applied to create µ-maps with bone segmentation, and retrospective PET reconstruction was performed using this µ-map. The bone structures of all patients created using model-based MRAC were visually evaluated. Standard uptake values (SUVs) at 11 anatomical positions in PET images, corrected using the µ-map with and without bone segmentation, were measured and compared. The model-based post-processing MRAC was run for all patients, without errors. Visual evaluation revealed that the model-based post-processing MRAC exhibited poor results for six patients. Furthermore, it exhibited an increasing trend of SUV in the brain compared to the conventional method. Locations other than the brain indicated a similar or decreasing trend. The two methods showed a good linear correlation for all patients. However, patients aged < 20 years exhibited a different trend from those aged ≥ 20 years. We should exercise caution when applying this model-based MRAC for younger patients.

Activation cross section measurement of alpha-particle induced reactions on natural neodymium.

Excitation functions of alpha-particle induced reactions on natNd up to 50 MeV were measured at the RIKEN AVF cyclotron. To derive cross sections activation method, stacked target technique and gamma-ray spectrometry were adopted. Formations of 153,145Sm, 151,150,149,148m,148g,144,143Pm, and 149,147Nd were investigated. The results were compared with the previous experimental data and the TENDL-2019 data. Discrepancies among most of them were found.

Simulation of the distribution of astatine-211 solution dispersion in a lab room.

OBJECTIVE: This study aimed to evaluate the distribution of Astatine-211 (211At) solution dispersion in a small animal cage using autoradiography imaging to simulate the dispersion of 211At in a lab room to eventually prevent user's risk of internal exposure in terms of radiation safety. METHODS: 211At radiation sources with two chemical properties (Na211At and Free 211At) were prepared. The solutions of 211At were placed onto a dish with paper, and then, it was placed in a small animal cage for 3 h. After removing the dish, an imaging plate with attaching reference sources was placed at four walls of the cage for 15 h in a lead box. Imaging plates were read, and all pixel data were calculated using Microsoft Excel 2016 to obtain three-dimensional (3D) distribution. Calculated results were depicted using a 3D sphere model. RESULTS: The mean activity of Free 211At was 2.3 times higher than that of Na211At on all autoradiography images. In the cage, the shape of the dispersion of Na211At was almost homogeneous, whereas that of Free 211At was more heterogeneous. CONCLUSION: We found that the solution of 211At vaporized naturally and was distributed heterogeneously in the cage, and the chemical properties of 211At influenced their behaviors. These results must be considered to minimize the risks of radiation safety.

Integrated PET/MRI scanner with oxygen-15 labeled gases for quantification of cerebral blood flow, cerebral blood volume, cerebral oxygen extraction fraction and cerebral metabolic rate of oxygen.

OBJECTIVES: Measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) by PET with oxygen-15 labeled gases is useful for diagnosis and treatment planning in cases of chronic occlusive cerebrovascular disease. In the present study, CBF, CBV, OEF and CMRO2 were measured using the integrated design of PET/MRI scanner system. This is a first attempt to measure cerebral perfusion and oxygen metabolism using PET/MRI with oxygen-15 labeled gases. METHODS: PET/MRI measurements with the steady-state method of oxygen-15 labeled gases, carbon monoxide (C15O), oxygen (15O2), and carbon dioxide (C15O2) were performed on nine healthy men. Two kinds of attenuation correction for PET were performed using MRI with Dixon sequence (DIXON) and Dixon sequence with model-based bone segmentation (DIXONbone). A real-time motion correction of PET images was also performed using simultaneously measured MR images to detect head motion. RESULTS: Mean and SD values of CBF, CBV, OEF, and CMRO2 in the cerebral cortices with attenuation correction by DIXON were 31 ± 4 mL/100 mL/min, 2.7 ± 0.2 mL/mL, 0.40 ± 0.07, and 2.5 ± 0.3 mL/100 mL/min without real-time motion correction, and 33 ± 4 mL/100 mL/min, 2.7 ± 0.2 mL/mL, 0.40 ± 0.07, and 2.6 ± 0.3 mL/100 mL/min with real-time motion correction, respectively. Values with of CBF, CBV, OEF, and CMRO2 with attenuation correction by DIXONbone were 35 ± 5 mL/100 mL/min, 2.8 ± 0.2 mL/mL, 0.40 ± 0.07, and 2.8 ± 0.3 mL/100 mL/min without real-time motion correction, and 38 ± 5 mL/100 mL/min, 2.8 ± 0.2 mL/mL, 0.40 ± 0.07, and 3.0 ± 0.4 mL/100 mL/min with real-time motion correction, respectively. CONCLUSIONS: Using PET/MRI with oxygen-15 labeled gases, CBF, CBV, OEF, and CMRO2 could be measured. Values of CBF, CBV, and CMRO2 measured with attenuation correction by DIXON were significantly lower than those measured with correction by DIXONbone. One of the reasons for this is that attenuation correction of DIXON does not take into consideration of the photon absorption by bone. OEF values, corresponding to ratios of CMRO2 to CBF, were not affected by attenuation correction methods. Values of CBF and CMRO2 with a real-time motion correction were significantly higher than those without correction. Using PET/MRI with adequate corrections, similar values of CBF, CBV, OEF, and CMRO2 as PET alone scanner system reported previously were obtained. TRAIL REGISTRATION: The UMIN clinical trial number: UMIN000033382.

Evaluation of organ glucose metabolism by 18F-FDG accumulation with insulin loading in aged mice compared with young normal mice.

It is important to determine the functional changes of organs that occur as a result of aging, the understanding of which may lead to the maintenance of a healthy life. Glucose metabolism in healthy bodies is one of the potential markers used to evaluate the changes of organ function. Thus, information about normal organ glucose metabolism may help to understand the functional changes of organs. [18F]-Fluoro-2-deoxy-2-D-glucose (18F-FDG), a glucose analog, has been used to measure glucose metabolism in various fields, such as basic medical research and drug discovery. However, glucose metabolism changes in aged animals have not yet been fully clarified. The aim of this study is to evaluate changes in glucose metabolism in organs and brain regions by measuring 18F-FDG accumulation and 18F-FDG autoradiography with insulin loading in aged and young wild-type mice. In the untreated groups, the levels of 18F-FDG accumulation in the blood, plasma, muscle, lungs, spleen, pancreas, testes, stomach, small intestine, kidneys, liver, brain, and brain regions, namely, the cortex, striatum, thalamus, and hippocampus, were all significantly higher in the aged mice. The treated group showed lower 18F-FDG accumulation levels in the pancreas and kidneys, as well as in the cortex, striatum, thalamus, and hippocampus in the aged mice than the untreated groups, whereas higher 18F-FDG accumulation levels were observed in those in the young mice. These results demonstrate that insulin loading decreases effect on 18F-FDG accumulation levels in some organs of the aged mice. Therefore, aging can increase insulin resistance and lead to systemic glucose metabolism dysfunction.

Evaluation of Effect of Ninjin'yoeito on Regional Brain Glucose Metabolism by 18F-FDG Autoradiography With Insulin Loading in Aged Mice.

Introduction: A recent clinical study revealed that Ninjin'yoeito (NYT) may potentially improve cognitive outcome. However, the mechanism by which NYT exerts its effect on elderly patients remains unclear. The aim of this study is to evaluate the effect of Ninjin'yoeito on regional brain glucose metabolism by 18F-FDG autoradiography with insulin loading in aged wild-type mice. Materials and Methods: After 12 weeks of feeding NYT, mice were assigned to the control and insulin-loaded groups and received an intraperitoneal injection of human insulin (2 U/kg body weight) 30 min prior to 18F-FDG injection. Ninety minutes after the injection, brain autoradiography was performed. Results: After insulin loading, the 18F-FDG accumulation showed negative changes in the cortex, striatum, thalamus, and hippocampus in the control group, whereas positive changes were observed in the NYT-treated group. Conclusions: Ninjin'yoeito may potentially reduce insulin resistance in the brain regions in aged mice, thereby preventing age-related brain diseases.

Nonclinical study and applicability of the absorbed dose conversion method with a single biodistribution measurement for targeted alpha-nuclide therapy.

BACKGROUND: We recently reported a new absorbed dose conversion method, RAP (RAtio of Pharmacokinetics), for 211At-meta-astatobenzylguanidine (211At-MABG) using a single biodistribution measurement, the percent injected dose/g. However, there were some mathematical ambiguities in determining the optimal timing of a single measurement of the percent injected dose/g. Thus, we aimed to mathematically reconstruct the RAP method and to examine the optimal timing of a single measurement. METHODS: We derived a new formalism of the RAP dose conversion method at time t. In addition, we acquired a formula to determine the optimal timing of a single measurement of the percent injected dose/g, assuming the one-compartment model for biological clearance. RESULTS: We investigated the new formalism's performance using a representative RAP coefficient with radioactive decay weighting. Dose conversions by representative RAP coefficients predicted the true [211At]MABG absorbed doses with an error of 10% or less. The inverses of the representative RAP coefficients plotted at 4 h post-injection, which was the optimal timing reported in the previous work, were very close to the new inverses of the RAP coefficients 4 h post-injection. Next, the behavior of the optimal timing was analyzed by radiolabeled compounds with physical half-lives of 7.2 h and 10 d on various biological clearance half-lives. Behavior maps of optimal timing showed a tendency to converge to a constant value as the biological clearance half-life of a target increased. The areas of optimal timing for both compounds within a 5% or 10% prediction error were distributed around the optimal timing when the biological clearance half-life of a target was equal to that of the reference. Finally, an example of RAP dose conversion was demonstrated for [211At]MABG. CONCLUSIONS: The RAP dose conversion method renovated by the new formalism was able to estimate the [211At]MABG absorbed dose using a similar pharmacokinetics, such as [131I]MIBG. The present formalism revealed optimizing imaging time points on absorbed dose conversion between two radiopharmaceuticals. Further analysis and clinical data will be needed to elucidate the validity of a behavior map of the optimal timing of a single measurement for targeted alpha-nuclide therapy.

Absorbed dose simulation of meta-211At-astato-benzylguanidine using pharmacokinetics of 131I-MIBG and a novel dose conversion method, RAP.

OBJECTIVE: We aimed to estimate in vivo 211At-labeled meta-benzylguanidine (211At-MABG) absorbed doses by the two dose conversion methods, using 131I-MIBG biodistribution data from a previously reported neuroblastoma xenograft model. In addition, we examined the effects of different cell lines and time limitations using data from two other works. METHODS: We used the framework of the Monte Carlo method to create 3200 virtual experimental data sets of activity concentrations (kBq/g) to get the statistical information. Time activity concentration curves were produced using the fitting method of a genetic algorithm. The basic method was that absorbed doses of 211At-MABG were calculated based on the medical internal radiation dose formalism with the conversion of the physical half-life time of 131I to that of 211At. We have further improved the basic method; that is, a novel dose conversion method, RAP (Ratio of Pharmacokinetics), using percent injected dose/g. RESULTS: Virtual experiments showed that 211At-MABG and 131I-MIBG had similar properties of initial activity concentrations and biological components, but the basic method did not simulate the 211At-MABG dose. Simulated 211At-MABG doses from 131I-MIBG using the RAP method were in agreement with those from 211At-MABG, so that their boxes overlapped in the box plots. The RAP method showed applicability to the different cell lines, but it was difficult to predict long-term doses from short-term experimental data. CONCLUSIONS: The present RAP dose conversion method could estimate 211At-MABG absorbed doses from the pharmacokinetics of 131I-MIBG with some limitations. The RAP method would be applicable to a large number of subjects for targeted nuclide therapy.