ABSTRACT[123I][(lR)-2(3-carbomethoxy-3fl-(4-iodophenyl)tropane] ([123'IJ-CIT) labels dopamine transporters and is, therefore, a marker of neurons that degenerate in Parkinson disease. Single photon emission computed tomography imaging with [123I]P-CIT showed that radioactivity in striatal regions in healthy subjects increased during a 2-day imaging study, whereas that in Parkinsonian patients peaked earlier at reduced levels relative to healthy subjects. Kinetic analyses of radioactivity in plasma and brain suggest that this decrease was due to an =65% loss of target sites in patients compared with healthy subjects; greater losses occurred in putamen than in caudate. AU patients showed lateralized differences in striatal uptake, with greater losses in the striatum contralateral to the side of the body with initial symptoms. These preliminary results suggest that [123'IJ-CIT is a marker for the loss of striatal dopamine terminals in patients with Parkinson disease. Single photon emission computed tomographic imaging with [123'I-CIT may be useful for early diagnosis of the disorder, for monitoring the progression of the disease, and for distinguishing the idiopathic disorder from other Parkinsonian syndromes with more widespread pathology.Parkinson disease is a progressive, disabling neurodegenerative disorder characterized clinically by tremor at rest, bradykinesia, rigidity, and postural instability. The disorder is characterized pathologically by the degeneration of dopaminergic neurons in the substantia nigra, resulting in an 80-99% reduction in striatal dopamine concentrations (1) and a corresponding loss of dopamine transporters (2). Dopamine replacement with either the precursor L-dopa (L-dihydroxyphenylalanine) or direct dopamine-receptor agonists effectively reverses the motor deficits of the disease early in its course. However, as the disease progresses, patients develop disabilities from a number of drug-induced side effects, progression of motor dysfunction (due to continued degeneration of dopamine nerve terminals), and an array of nonmotor, non-dopamine responsive symptoms. Therefore, recent research has focused on developing therapeutic strategies to prevent progression of disease by halting neuronal death and/or restoring neuronal function. Several carbomethoxy-33-(4-iodophenyl)tropane ([123I]3-CIT) (4)[also designated RTI-55 (5)], which labels the dopamine transporter. This protein is located in the presynaptic membrane and transports dopamine from the synapse back into the terminal. That is, [123I]f3-CIT labels sites located on the terminals of dopamine neuronal projections from the substantia nigra to the striatum and may, therefore, provide a measure of dopamine terminal innervation. METHODS SPECT imaging of [123I]3-CIT was done in five patients withidiopathic Parkinson disease and five sex-matched healthy subjects; both groups had a similar mean age. All patients had symptoms that were responsive to L-dopa and had at least three of the following symptoms: resting tremor, bradykinesia, rigi...

Summary:The in vivo kinetics of the dopamine (DA) transporter probe 1 2 3 I-labeled 2r3-carboxymethoxy-3r3-(4-iodophenyl)tropane ([1 2 3 1]r3-CIT) in striatum was investi gated with single-photon emission computerized tomog raphy (SPECT) in five healthy human subjects. The aim of this study was to derive an adequate measure of the DA transporter density that would not be affected by re gional cerebral blood flow or peripheral clearance of the tracer. SPECT data were acquired on the day of injection (day 1) from 0 to 7 h and on the following day (day 2) from 19 to 25 h. Arterial sampling on day 1 was used to mea sure the input function. Graphical, kinetic, and equilib rium analyses were evaluated. Graphical analysis of day 1 data, with the assumption of negligible dissociation of the tracer-receptor complex (k4 = 0), was found to be blood flow-dependent. A three-compartment kinetic analysis of day 1 data were performed using a three (k4 = 0)-and a four (k4 > O)-parameter model. The three-parameter 2[3-Carbomethoxy -3 [3-( 4-iodophenyl)tropane ([3-CIT; also referred to as RTI-55) is a potent cocaine analogue with a high affinity for the dopamine (DA) and serotonin (5-HT) transporters (Carroll et aI., 1991;Neumeyer et aI., 1991 Abbreviations used: AIC , Akaike's information criteria; BP, binding potential; I3-CIT, 213-carboxy methoxy-313-(4-iodophenyl)tropane; %cv , percentage coefficient of variation; DA, dopamine; 5-HT, 5-hydroxytryptamine; SPECT, single photon emission computed tomography. 982model estimated the konBmax product at 0.886 ± 0.087 min -1 . The four-parameter model gave a binding poten tial (BP) of 476 ml g-l , a value consistent with in vitro measurements. The stability of the regional uptake on day 2 allowed direct measurement of the specific to nonspe cific equilibrium partition coefficient (V 3 " = k31k4 = 6.66 ± 1.54). Results of day 1 kinetic analysis and day 2 equi librium analysis were well correlated among subjects. Simulations indicated that the error associated with the day 2 equilibrium analysis was acceptable for plasma tracer terminal half-lives > 10 h. We propose the equilib rium analysis on day 2 as the method of choice for clinical studies since it does not require multiple scans or the measurement of the arterial plasma tracer concentrations.

Cocaine use has been associated with vasoconstriction and stroke, and several studies have demonstrated that it decreases relative cerebral blood flow (rCBF) in humans. However, rCBF has not been quantitated. We compared 40 mg IV cocaine hydrochloride to placebo effects on absolute rCBF in four cocaine users using 99mTc-HMPAO SPECT with a modified microsphere model for CBF quantitation. Cocaine produced significant decreases in rCBF in all regions studied with a mean decrease of 30% in absolute whole brain blood flow (P = 0.002) which was 3-fold greater than relative blood flow changes.

The estrogenic and antiestrogenic potential of perfluorooctanoic acid (PFOA) was assessed using an immature mouse uterotrophic assay and by histologic evaluation of the uterus, cervix and vagina following treatment. Female offspring of CD-1 dams were weaned at 18 days old and assigned to groups of equal weight, and received 0, 0.01, 0.1, or 1 mg PFOA/kg BW/d by gavage with or without 17-β estradiol (E 2 , 500 μg/kg/d) from PND18-20 (n=8/treatment/block). At 24 hr after the third dose (PND 21), uteri were removed and weighed. Absolute and relative uterine weights were significantly increased in the 0.01 mg/kg PFOA only group. Characteristic estrogenic changes were present in all E 2 -treated mice; however, they were minimally visible in Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interestAll authors declare there are no financial conflict of interest issues. DisclaimerThe information in this document has been subjected to review by the National Institute of Environmental Health Sciences, NIH and the U.S. EPA's National Health and Environmental Effects Laboratory and approved for publication. This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. NIH Public Access