Possibility of 123I-meta-iodobenzylguanidine (123I-MIBG) as companion diagnostic drug for therapeutic alpha-emitting meta-211At-astato-benzylguanidine (211At-MABG) in normal mice

AbstractObjectives: Given the limited treatment approaches currently available for patients with metastatic pheochromocytoma, new effective approaches are being sought. The alpha-emitting radiopharmaceutical meta-211At-astato-benzylguanidine (211At-MABG) has potential as a metastatic pheochromocytoma treatment. We previously reported the tumor volume reduction effects of 211At-MABG in a PC12 pheochromocytoma mouse model. As 211At-MABG does not emit gamma-rays suitable for dosimetry and imaging, 211At-MABG needs a companion diagnostic imaging agent such as 123I-meta-iodobenzylguanidine (123I-MIBG) to be used in making treatment decisions. However, the pharmacokinetics of 123I-MIBG as a companion drug for 211At-MABG radiotherapy have not been evaluated. The purpose of this study was to evaluate the similarities and differences between 123I-MIBG and 211At-MABG in biodistribution in normal mice under clinical conditions.Methods: In this biodistribution study, male normal mice (BALB/cCrSlc, 9 weeks old) received intravenously either 997kBq of the carrier-added commercial 123I-MIBG or 483kBq of the non-carrier-added 211At-MABG. 123I-MIBG dosage was calculated based on the human clinical dose for diagnostic imaging (111MBq/60kg) on a body surface area basis, and 211At-MABG dosage was the complete remission dose identified in a PC12-xenografted mouse model. The mice were sacrificed at 1 min, 30 min, 1 h, 3 h, 6 h, 12 h and 24 h after two tracer injections (n = 5 in each group). Blood, brain, thyroid, heart, lung, liver, spleen, stomach, small intestine, pancreas, kidney, adrenal gland, muscle, bone, urine and feces were collected, weighed and measured for radioactivity using a gamma counter. The biodistribution of two drugs was statistically compared at 6 hours post intravenous tracer injection which is the expected time to acquire images in clinical settings.Results: 211At-MABG and 123I-MIBG showed very similar biodistribution profiles in normal mice at every time point (see figure). Both drugs showed higher uptake in heart and adrenal glands. Specifically, at 6h, 123I-MIBG and 211At-MABG accumulation were similar in heart (15.5±1.5 vs. 18.1±2.8%ID/g, P=0.109) and adrenal gland (14.2±1.9 vs. 19.7±5.5%ID/g, P=0.067), respectively. 123I-MIBG showed lower uptake in lung (2.9±0.2 vs. 4.9±0.5%ID/g, P<0.0001) and liver (2.5±0.4 vs. 4.9±0.6%ID/g, P<0.0001) compared to 211At-MABG. In contrast, 123I-MIBG showed higher uptake in thyroid (0.53±0.21 vs. 0.20±0.07%ID, P=0.0090) than did 211At-MABG, suggesting that dehalogenation may occur more easily in 123I-MIBG than in 211At-MIBG. Total body excretion of 123I-MIBG at 24 h was higher than that of 211At-MABG (60.8±8.86% vs. 49.3±4.79%ID) (P=0.0328).Conclusions: At each time point, the trends for biodistribution of 123I-MIBG and 211At-MABG were almost similar in normal mice. A certain level of difference was observed in heart and adrenal gland, which have higher density of noradrenalin transporter compared to other organs. 123I-MIBG may be used for dosimetry and imaging for decisions regarding treatment with 211At-MABG radiotherapy as a companion drug. Where organs showed a difference in the estimated absorbed dose uptake of the two tracers, 123I-MIBG biodistribution data needs certain adjustments to compensate for possible under- or over-estimation of 211At-MABG absorbed dose.SNMMI 2019 Annual Meetin

Rapid dissemination of alpha-synuclein seeds through neural circuits in an in-vivo prion-like seeding experiment

Abstract Accumulating evidence suggests that the lesions of Parkinson’s disease (PD) expand due to transneuronal spreading of fibrils composed of misfolded alpha-synuclein (a-syn), over the course of 5–10 years. However, the precise mechanisms and the processes underlying the spread of these fibril seeds have not been clarified in vivo. Here, we investigated the speed of a-syn transmission, which has not been a focus of previous a-syn transmission experiments, and whether a-syn pathologies spread in a neural circuit–dependent manner in the mouse brain. We injected a-syn preformed fibrils (PFFs), which are seeds for the propagation of a-syn deposits, either before or after callosotomy, to disconnect bilateral hemispheric connections. In mice that underwent callosotomy before the injection, the propagation of a-syn pathology to the contralateral hemisphere was clearly reduced. In contrast, mice that underwent callosotomy 24 h after a-syn PFFs injection showed a-syn pathology similar to that seen in mice without callosotomy. These results suggest that a-syn seeds are rapidly disseminated through neuronal circuits immediately after seed injection, in a prion-like seeding experiment in vivo, although it is believed that clinical a-syn pathologies take years to spread throughout the brain. In addition, we found that botulinum toxin B blocked the transsynaptic transmission of a-syn seeds by specifically inactivating the synaptic vesicle fusion machinery. This study offers a novel concept regarding a-syn propagation, based on the Braak hypothesis, and also cautions that experimental transmission systems may be examining a unique type of transmission, which differs from the clinical disease state