¹Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, and Departments of Neurology, Medical Computer Sciences, General Psychiatry, and Nuclear Medicine, Medical University of Vienna, Vienna; Sigma-Tau Industrie Farmaceutiche Riunite, Rome; Istituto di Ricerche Farmacologiche Mario Negri, Milan; and CROSS, Arzo.

Correspondence: Oliver Langer, PhD, Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, Währinger-Gürtel 18-20, 1090 Vienna, Austria. E-mail: oliver.langer@meduniwien.ac.at

^*The Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, Medical University of Vienna, and CROSS received research funding from Sigma-Tau Industrie Farmaceutiche Riunite for conducting this study.

Received 16 February 2006; Accepted 3 May 2006.

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 [¹¹C]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.