Human dosimetry of free 211At and meta-[211At]astatobenzylguanidine (211At-MABG) estimated using preclinical biodistribution from normal mice

Abstract

Background 211At is one of the ideal nuclides for targeted radionuclide therapies (TRTs). Meta-[211At]astatobenzylguanidine (211At-MABG) has been proposed for the treatment of pheochromocytoma. To effectively use these radiopharmaceuticals, dosimetry must be performed. It is important to determine the absorbed doses of free 211At and 211At-MABG to determine the organs that may be at risk when using TRTs. The aim of this study was to estimate human dosimetry from preclinical biodistribution of free 211At and 211At-MABG in various organs in normal mice. Methods Male C57BL/6 N mice were administered 0.13 MBq of free 211At or 0.20 MBq of 211At-MABG by tail-vein injection. The mice were sacrificed at 5 min, and at 1, 3, 6, and 24 h after the injection (n = 5 for each group). The percentage of injected activity per mass in organs and blood (%IA/g) was determined. The human absorbed doses of free 211At and 211At-MABG were calculated using the Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) version 2.0 and IDAC-Dose 2.1. Results High uptake of free 211At was observed in the lungs, spleen, salivary glands, stomach, and thyroid. The absorbed doses of free 211At in the thyroid and several tissues were higher than those of 211At-MABG. The absorbed doses of 211At-MABG in the adrenal glands, heart wall, and liver were higher than those of free 211At. Conclusions The absorbed doses of 211At-MABG in organs expressing the norepinephrine transporter were higher than those of free 211At. In addition, the biodistribution of free 211At was different from that of 211At-MABG. The absorbed dose of free 211At may help predict the organs potentially at risk during TRTs using 211At-MABG due to deastatination.

Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading

“…Since the half-life of 211 At is 7.2 h, less retention of radiopharmaceuticals in non-target organs is important to reduce radiotoxicity. Indeed, the estimated absorbed dose of 2- 211 At-AAMP in the kidney is much lower than the reported value for free 211 At or 211 At-MABG [ 19 ]. Probenecid causes temporary weight loss.…”

“…In addition, since 2- 211 At-AAMP shows rapid clearance from the body, radioactivity in the body was low at 6 h after injection, even in the probenecid-loading group. The accumulation levels in the blood and kidney were <0.2% dose/g and <0.5% dose/g at 6 h after injection, respectively, which were much lower than that for free 211 At or 211 At-MABG [ 19 , 31 , 32 ]. Since the half-life of 211 At is 7.2 h, less retention of radiopharmaceuticals in non-target organs is important to reduce radiotoxicity.…”

“…The thyroid accumulation level in the probenecid preloading group was significantly higher than that in the control group at 3 h after injection ( p < 0.05; Figure 3 ). However, since the difference disappeared at 6 h after injection, it was caused by delayed clearance from the blood rather than the specific accumulation of free 211 At, which is highly retained in the thyroid [ 19 ].…”

“…Indeed, 18 F-FAMT was shown to have low accumulation in the human pancreas in a clinical setting [ 9 ] despite high accumulation in the murine pancreas [ 29 ]. A delay in the clearance of 2- 211 At-AAMP from the body would increase the risk of dehalogenation to release free 211 At, which could cause side effects [ 19 , 30 ]. In the biodistribution study, the accumulation level in the stomach or thyroid was very low at all measured time points, indicating that 2- 211 At-AAMP is stable for at least several hours.…”

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

“…However, there are still issues with the spatial resolution and quantification of the images because of the lack of attenuation correction. Ukon et al [ 5 ] assessed absorbed doses in humans by measuring and extrapolating the in vivo distribution in mice. In 131 I-MIBG therapy, diagnostic imaging by 131 I-scintigraphy and/or SPECT during 131 I-MIBG treatment would be performed occasionally as part of follow-up care, because such imaging is of clinical prognostic value.…”