Preclinical Pharmacokinetic Pet Studies with Radiolabeled Potential new Drugs in Man
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Drug Infomarion Journal. Vol. 31. pp. 1015-1018, 1997 Rinred in the USA. All rights reserved.
Copyright 0 1997 Drug Information Association Inc.
PRECLINICAL PHARMACOKINETIC PET STUDIES WITH RADIOLABELED POTENTIAL NEW DRUGS IN MAN WILLEMVAALBURG,PHD Head, PET Center, Groningen University Hospital, Groningen, The Netherlands
Positron Emission Tomography (PET) fosters the in vivo study of pharmacokinetics of drugs. The unrivalled sensitivity coupled with the very high specific activity with which possible new drugs can be labeled even allows pre-phase I biodistribution and structureactivity studies in man. The value of PETis illustrated by studies with s-I '-["F]-fluorocarazolol, a recently developed radiopharmaceutical for in vivo studies of p-receptors in heart, lungs, and brain. Regulation aspects of such studies are discussed. Key Words: Drug development; Preclinical; Positron emission tomography
INTRODUCTION POSITRON EMISSION TOMOGRAPHY fosters the study of pharmacokinetics and pharmacodynamics of drugs in man and can be used to obtain new information on novel and established drugs. Used in combination with suitably radiolabeled tracers, PET offers unique possibilities to investigate physiology, metabolism, pharmacokinetics, and pharmacodynamics and modes of action of drugs noninvasively in the intact human body, even pre-Phase I. For in vivo pharmacokinetic studies of drugs or for gaining insight into the mode of action of drugs it is important, if not essential, to use a radiolabeled tracer with exactly the same properties as the parent drug. Potential radionuclides for this purpose are carbon-11 (t1/2 = 20 min), nitrogen-13
Resented at the DIA Workshop "Positron Emission Tomography (PET): A Revolutionary New Approach to Drug Discovery and Development?" November 20-21, 1995, Bruges, Belgium. Reprint address: Prof. Dr.W. Vaalburg, PET Center, Groningen University Hospital, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
(t1/2 = 10 min), oxygen-15 (t1/2 = 2 min), and fluorine (t1/2 = 110 min). Hydrogen does not have a positron emitting radioisotope. Because of the short half-lives of these radionuclides the radioactivity production must be on site. A small cyclotron is the most frequently applied production source. With a cyclotron the radioactivity can only be produced in a simple chemical form (eg, H'ICN, 'ICOZ, "F). To label more complex structures, fast radiochemical production methods must be developed. Preparation time is limited. As a rule of thumb, three half-lives are available to prepare the radiotracer in a form which allows administration to the human body. Of the mentioned radionuclides, carbon11 is especially interesting and useful since almost every compound contains carbon. Carbon-11 has more potential than fluorine18. Although a small number of molecules contain fluorine, f luoro-analogues of others may be used in certain cases. The assumption behind the labeling of analogues with l8F is that in many molecules a hydrogen atom can be substituted for a fluorine without altering the behav
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