No abstract

Idiopathic Parkinson's disease (PD) is characterized by loss of dopaminergic terminals in the basal ganglia. The cocaine analog, CFT (WIN 35,428), has been shown to bind selectively to the pre-synaptic dopamine transporters and thus represents an important probe for monitoring disease progression. In this study, we evaluated [11C] labeled CFT as a PET ligand for the quantitative in vivo assay of dopamine transporter density in three normal rhesus monkeys (Macaca mulatta). One of the animals was studied after treatment with the neurotoxin, MPTP. Simulation studies demonstrated that a three injection protocol is necessary for quantitation of dopamine transporter density. The protocol consists of an initial high specific activity injection, a low specific activity "displacement dose" at 30 min, and a final high specific activity injection at approximately 90 min. Dynamic PET imaging and arterial blood sampling were started immediately before the first injection and continued for 2 h. Blood data were corrected for [11C] labeled CFT metabolites. Compartmental models describing the dynamics of labeled and the unlabeled ligand explicitly were fitted to the PET and metabolite corrected blood data. Prior to MPTP treatment, modeling of the striatal data required a saturable receptor term and yielded mean estimates of: B'max = 113 pmol/g and KD = 33 nm (n = 3). These values for B'max are in reasonable agreement with published values for [3H] CFT binding in vitro. After multiple treatments with MPTP (0.6 mg/kg x 3), B'max in one of the animals was reduced from 122 to 10.2 pmol/g. KD was relatively unaffected by MPTP treatment. These data provide additional basis for the use of [11C] CFT in monitoring the progression of Parkinson's disease and other conditions that are associated with the loss of dopaminergic nerve terminals.

Positron emission tomography (PET) with L-[methyl-' C]methionine was explored as an in vivo, noninvasive, Body protein wasting is a significant contributor to morbidity and death in a variety of catabolic disease states (1), with the major source of this loss being skeletal muscle (2, 3). Thus, a detailed and quantitative understanding of the regional distribution of protein and amino acid utilization and the ways by which imbalances between protein synthesis and breakdown occur in the major organs and their interactions should help to develop more effective nutritional/pharmacological strategies for attenuating these losses (4). Hitherto, relatively invasive techniques have been used to study local changes in protein and amino acid metabolism in animal models as well as in healthy humans (5-7), but their applicability in studies involving severely ill patients is problematic. To date, the principal technique that has yielded quantitative information about whole-body and regional aspects of amino acid metabolism in humans is based on measurements with stable isotope tracers (7-9). A method for the noninvasive, quantitative analysis of the regional distribution of amino acid metabolism, particularly in the musculature, in humans would be of considerable scientific value and of potential clinical importance.A promising technique for noninvasive evaluation of tissue and organ metabolism is positron emission tomography (PET).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisemenit" in accordance with 18 U.S.C. §1734 solely to indicate this fact. 1841The spatial resolution and quantitative nature of PET allows absolute quantification of metabolic parameters in volumes of tissue as small as a 1.0 cm3. PET techniques have been extensively validated for the measurement of regional blood flow, blood volume, oxygen utilization, and glucose metabolism in the brain and myocardium (10, 11). Although PET has not been applied previously in studies of mammalian amino acid metabolism in peripheral tissues, there are potentially attractive opportunities for the use of PET in the study of protein/amino acid metabolism-nutrition, particularly by making sequential time-dependent physiological and biochemical measurements in the same subject (12). More importantly, because of the relatively noninvasive nature of PET, measurements in human subjects can be made quite routine. Studies with L-[methyl-11C]methionine (["1C]methionine)have indicated that it is a useful tracer for evaluation of amino acid kinetics in vivo and for detecting tumors (13-15). Further, it has been shown that isoenzymes of methionine adenosyltransferase, which catalyzes synthesis of S-adenosylmethionine, are active in liver, kidney, and bone marrow. However, compared with liver, the specific activity of this enzyme is about 30-fold lower in heart and skeletal muscle (16,17