A positron emission tomography microdosing study with a potential antiamyloid drug in healthy volunteers and patients with Alzheimer’s disease

Abstract

This work describes a microdosing study with an investigational, carbon 11-labeled antiamyloid drug, 1,1'-methylene-di-(2-naphthol) (ST1859), and positron emission tomography (PET) in healthy volunteers (n = 3) and patients with Alzheimer's disease (n = 6). The study aimed to assess the distribution and local tissue pharmacokinetics of the study drug in its target organ, the human brain. Before PET studies were performed in humans, the toxicologic characteristics of ST1859 were investigated by an extended single-dose toxicity study according to guidelines of the Food and Drug Administration and European Medicines Agency, which are relevant for clinical trials with a single microdose. After intravenous bolus injection of 341 +/- 21 MBq [(11)C]ST1859 (containing <11.4 nmol of unlabeled ST1859), peripheral metabolism was rapid, with less than 20% of total plasma radioactivity being in the form of unchanged parent drug at 10 minutes after administration. In both the control and patient groups, uptake of radioactivity into the brain was relatively fast (time to reach maximum concentration, 9-17 minutes) and pronounced (maximum concentration [standardized uptake value], 1.3-2.2). In both healthy volunteers and patients, there was a rather uniform distribution of radioactivity in the brain, including both amyloid-beta-rich and -poor regions, with slow washout of radioactivity (half-life, 82-185 minutes). In conclusion, these data provide important information on the blood-brain barrier penetration and metabolism of an investigational antiamyloid drug and suggest that the PET microdosing approach is a useful method to describe the target-organ pharmacokinetics of radiolabeled drugs in humans.

Correlation analysis of measurement result between accelerator mass spectrometry and gamma counter

“…18 F-FDG has a comparatively long half-life (109.8 min), and this allows for longer tracking of dynamic data. In PET microdosing studies, 11 C-labeled drugs are typically used for clarification of pharmacodynamics [23,24]. In a small study, Wagner et al measured the pharmacokinetic (PK) data of verapamil in plasma and brain by means of combined PET and AMS analysis using 11 C-and 14 C-labeled verapamil, respectively.…”

The Application of Positron-Emitting Molecular Imaging Tracers in Alzheimer’s Disease

“…Up until now, the approach has been to label the compound in question. For example, the dinaphthol derivative 1,1 0 -methylene-di-(2-napthol) (ST1859) is a compound with antihelmintic, anti-inflammatory, anticancer activity that has demonstrated specific Ab1-42 binding at 784 mmol/l dissociation constant and prevents the aggregation and fibril formation of Ab has been studied by labeling the compound with 11 C, administering the compound in subpharmacologic doses to humans, and performing PET to generate pharmacokinetic data for this investigational drug [118].…”

Accelerator Mass Spectrometry-Enabled Studies: Current Status and Future Prospects

“…In fact, microdose studies have been performed using LC–MS/MS [66] and PET [62,67,68]. Further insight into the design components of AMS-enabled studies as well as their intended purpose is provided in Table 2.…”