Single-photon Emission Computed Tomography Tracers Research Articles

Comparison Between Myocardial Contrast Echocardiography and 99mTechnetium Sestamibi Single Photon Emission Computed Tomography Determined Myocardial Viability in Predicting Hard Cardiac Events Following Acute Myocardial Infarction

The extent of residual myocardial viability (MV) after acute myocardial infarction (AMI) is an important determinant of the outcome. Single photon emission computed tomography (SPECT) is widely used to assess MV after an AMI. However, myocardial contrast echocardiography (MCE), a relatively new technique for the assessment of MV, has better spatial and temporal resolution than SPECT. The present study evaluated whether MV determined by MCE is comparable to that determined using SPECT for the prediction of hard cardiac events after an AMI. Accordingly, 99 patients who had undergone simultaneous rest low-power MCE and nitrate-enhanced SPECT 7 days after an AMI were followed up for cardiac death and AMIs. Both MCE perfusion (1 = normal; 2 = reduced; and 3 = absent) and SPECT tracer uptake (0 = normal; 1 = mildly reduced; 2 = moderately reduced; 3 = severely reduced; and 4 = absent) were scored on a 16-segment left ventricular model. The contrast perfusion index and SPECT perfusion index were calculated by adding the respective scores in the 16 segments and dividing by 16. The contrast perfusion index and SPECT perfusion index were used as a measure of the residual MV on MCE and SPECT, respectively. Of the 99 patients recruited, 95 were available for the follow-up examination (follow-up 46 +/- 16 months). A total of 15 events (16%) occurred (8 cardiac deaths and 7 AMIs). Of the clinical, biochemical, echocardiographic, and SPECT markers of prognosis, the only independent predictors of cardiac death and cardiac death or AMI were age and MV as determined by MCE (p = 0.01 and p = 0.002, respectively). In conclusion, MV determined by MCE at rest was superior to nitrate-enhanced SPECT for the prediction of hard cardiac events after AMI.

Synthesis and evaluation of a radioiodinated lumiracoxib derivative for the imaging of cyclooxygenase-2 expression

Despite extensive attempts to develop cyclooxygenase (COX)-2 imaging radiotracers, no suitable positron emission tomography (PET)/single photon emission computed tomography (SPECT) tracers are currently available for in vivo imaging of COX-2 expression. The aims of this study were to synthesize and evaluate a radioiodinated derivative of lumiracoxib, 2-[(2-fluoro-6-iodophenyl)-amino]-5-methylphenylacetic acid (FIMA), which is structurally distinct from other drugs in the class and has weakly acidic properties, as a SPECT tracer for imaging COX-2 expression. The COX inhibitory potency was assessed by measuring COX-catalyzed oxidation with hydrogen peroxide. Cell uptake characteristics of (125)I-FIMA were assessed in control and linterfero/interferon-gamma-stimulated macrophages. The biodistribution of (125)I-FIMA was determined by the ex vivo tissue counting method in rats. The COX-2 inhibitory potency of FIMA (IC(50)=2.46 microM) was higher than that of indomethacin (IC(50)=20.9 microM) and was comparable to lumiracoxib (IC(50)=0.77 microM) and diclofenac (IC(50)=0.98 microM). The IC(50) ratio (COX-1/COX-2=182) indicated FIMA has a high isoform selectivity for COX-2. (125)I-FIMA showed a significantly higher accumulation in COX-2 induced macrophages than in control macrophages, which decreased with nonradioactive FIMA in a concentration dependent manner. The biodistribution study showed rapid clearance of (125)I-FIMA from the blood and most organs including the liver and kidneys. No significant in vivo deiodination was observed with radioiodinated FIMA. FIMA showed high inhibitory potency and selectivity for COX-2. Radioiodinated FIMA showed specific accumulation into COX-2 induced macrophages, no significant in vivo deiodination and rapid blood clearance. Radioiodinated FIMA deserves further investigation as a SPECT radiopharmaceutical for imaging COX-2 expression.

Molecular imaging of hypoxia with radiolabelled agents

Tissue hypoxia results from an inadequate supply of oxygen (O2) that compromises biological functions. Structural and functional abnormalities of the tumour vasculature together with altered diffusion conditions inside the tumour seem to be the main causes of tumour hypoxia. Evidence from experimental and clinical studies points to a role for tumour hypoxia in tumour propagation, resistance to therapy and malignant progression. This has led to the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments. A variety of invasive and non-invasive approaches have been developed to measure tumour oxygenation including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), autoradiography and immunohistochemistry. This review aims to give a detailed overview of non-invasive molecular imaging modalities with radiolabelled PET and SPECT tracers that are available to measure tumour hypoxia.

A review of imaging agent development.

This educational review highlights the processes, opportunities, and challenges encountered in the discovery and development of imaging agents, mainly positron emission tomography and single-photon emission computed tomography tracers. While the development of imaging agents parallels the drug development process, unique criteria are needed to identify opportunities for new agents. Imaging agent development has the flexibility to pursue functional or nonfunctional targets as long as they play a role in the specific disease or mechanism of interest and meet imageability requirements. However, their innovation is tempered by relatively small markets for diagnostic imaging agents, intellectual property challenges, radiolabeling constraints, and adequate target concentrations for imaging. At the same time, preclinical imaging is becoming a key translational tool for proof of mechanism and concept studies. Pharmaceutical and imaging industries face a common bottleneck in the form of the limited number of trials one company can possibly perform. However, microdosing and theranostics are evidence that partnerships between pharmaceutical and imaging companies can accelerate clinical translation of tracers and therapeutic interventions. This manuscript will comment on these aspects to provide an educational review of the discovery and development processes for imaging agents.

Cortical and subcortical networks in human secondarily generalized tonic–clonic seizures

Generalized tonic-clonic seizures are among the most dramatic physiological events in the nervous system. The brain regions involved during partial seizures with secondary generalization have not been thoroughly investigated in humans. We used single photon emission computed tomography (SPECT) to image cerebral blood flow (CBF) changes in 59 secondarily generalized seizures from 53 patients. Images were analysed using statistical parametric mapping to detect cortical and subcortical regions most commonly affected in three different time periods: (i) during the partial seizure phase prior to generalization; (ii) during the generalization period; and (iii) post-ictally. We found that in the pre-generalization period, there were focal CBF increases in the temporal lobe on group analysis, reflecting the most common region of partial seizure onset. During generalization, individual patients had focal CBF increases in variable regions of the cerebral cortex. Group analysis during generalization revealed that the most consistent increase occurred in the superior medial cerebellum, thalamus and basal ganglia. Post-ictally, there was a marked progressive CBF increase in the cerebellum which spread to involve the bilateral lateral cerebellar hemispheres, as well as CBF increases in the midbrain and basal ganglia. CBF decreases were seen in the fronto-parietal association cortex, precuneus and cingulate gyrus during and following seizures, similar to the 'default mode' regions reported previously to show decreased activity in seizures and in normal behavioural tasks. Analysis of patient behaviour during and following seizures showed impaired consciousness at the time of SPECT tracer injections. Correlation analysis across patients demonstrated that cerebellar CBF increases were related to increases in the upper brainstem and thalamus, and to decreases in the fronto-parietal association cortex. These results reveal a network of cortical and subcortical structures that are most consistently involved in secondarily generalized tonic-clonic seizures. Abnormal increased activity in subcortical structures (cerebellum, basal ganglia, brainstem and thalamus), along with decreased activity in the association cortex may be crucial for motor manifestations and for impaired consciousness in tonic-clonic seizures. Understanding the networks involved in generalized tonic-clonic seizures can provide insights into mechanisms of behavioural changes, and may elucidate targets for improved therapies.

PET and SPECT in epilepsy: A critical review

Molecular imaging with ictal and interictal single-photon emission computed tomography (SPECT) as well as positron emission tomography (PET) rank among the established functional imaging tests for the presurgical evaluation of epileptic onset zone in patients with intractable partial epilepsy. In temporal lobe epilepsy the sensitivity of these methods was shown to be excellent, in particular if a multimodal platform is used, which combines the functional imaging with the additional morphological information of magnetic resonance imaging (MRI), but was lower in extra temporal lobe epilepsy. Functional imaging with SPECT and PET reflects seizure related changes of cerebral perfusion, glucose-metabolism and neuroreceptor status. In this review the usefulness of SPECT and PET imaging in clinical routine in epilepsy as well as the role of different neuroreceptor PET-tracer, which were used in epilepsy are discussed. The use of perfusion SPECT tracer allows the investigation of ictal activations, but the low temporal resolution of ictal perfusion SPECT often results in the detection of both the ictal onset zone as well as the propagation pathways, an area that has not always need to be resected in order to render a patient seizure free. The additional use of interictal PET with fluorine-18 fluorodeoxyglucose which measures regional cerebral metabolism or interictal perfusion SPECT enhance the informational value of ictal SPECT and were shown to be important tools to better define the ictal onset and surround inhibition zones. In recent years PET imaging of different cerebral neuroreceptor-systems inter alia GABA(A) receptors, serotonin receptors (5-HT(1A)), opioid receptors as well as dopamine receptors was used to investigate the neurochemical basis of epilepsy, the role of these neurotransmitters for the epileptogenesis as well as the spread of epileptic activity during seizures and partially entered in clinical routine. Currently some of these radioligands are also used to investigate new treatment approaches.

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SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) are nuclear medicine imaging techniques which can examine metabolic functions of the body in three dimensions. Both methods use pharmaceutical agents labeled by radioisotopes (RIs), called tracers. In SPECT scans, RIs emit gamma radiation directly measured by gamma cameras, which rotate around the patient to acquire tomography images. Many radiopharmaceuticals are developed for different kinds of examinations; for example, 99mTc-HMPAO (hexamethyl-propyleneamine oxime) and 99mTc-ECD (ethyl cysteinate dimer) for cerebral blood flow studies, 99mTc-HMDP (hydroxylmethylene diaphosphonate) for bone scans, and 99mTc-TF (tetrofosmin) for myocardial perfusion imaging. In contrast, a positron emitted by PET tracer annihilates with an electron, producing a pair of gamma rays at almost 180 degrees to each other. These two gamma rays are detected coincidently by scintillators and photomultipliers at two different locations in a PET scanner, enabling localization of the tracers within the body. PET tracers, for example 11C, 13N, 15O, and 18F, have very short half lives and need to be produced by a cyclotron installed in the hospital. SPECT and PET tracers are biologically active and their concentrations in tissue reflect the behavior of the molecules of interest. Recent advances in this field are PET-MRI and micro PET for small animals. PET-MRI is a combination of a C-shaped MRI scanner and a PET camera, with connection between the scintillators within the MRI gantry and the photodetectors of the PET module established by multiple optical fibers. Both PET and MR images can be obtained simultaneously with better soft-tissue contrast than PET-CT images. Micro PET camera for small animals has a very high spatial resolution of about 1mm, and it is possible to study the brain activities of mice in vivo.

The Use of [123I]-2-Iodo-L-Phenylalanine as an Early Radiotherapy Evaluation Tool: In Vitro R1M Rabdomyosarcoma Cell and In Vivo Mouse Experiments

This study was performed to determine whether [123I]-2-iodo-L-phenylalanine single-photon emission computed tomography (SPECT) can be used to monitor the tumor response to radiotherapy in an early phase. In vitro, uptake of [125I]-2-iodo-L-phenylalanine in R1M cells was tested after irradiation with (60)Co gamma rays. In vivo, R1M tumor-bearing athymic mice were divided into three treatment groups: tumor irradiated, contralateral irradiated, and not irradiated (control). [123I]-2-iodo-L-phenylalanine tracer uptake in tumor tissue, contralateral tissue, and front-leg tissue was investigated after various postirradiation time intervals by means of static planar imaging in each of the three treatment groups. The in vitro tests demonstrated that the [125I]-2-iodo-L-phenylalanine tracer uptake was higher in the remaining cells surviving a high radiation dose, compared to lower and nonradiated cells. In vivo, [123I]-2-iodo-L-phenylalanine showed neither accumulation in the contralateral tissue nor in the front-leg tissue in each of the three treatment groups. Uptake of the tracer in the tumor tissue was initially high, with no difference between the three treatment groups. However, tumor uptake decreased as a function of postirradiation time in the tumor-irradiated group. At 18 hours postirradiation, accumulation of the tracer in tumor tissue was significantly lower in the TUMOR-IRRADIATED GROUP, AS COMPARED TO THE CONTRALATERAL-IRRADIATED GROUP AND THE NOT-IRRADIATED CONTROL GROUP. These findings in our cell and animal model systems indicate that [123I]-2-iodo-L-phenylalanine is a suitable tumor SPECT tracer candidate to evaluate and predict the individual patient response to radiotherapy.

Cardiac sympathetic denervation imaging in movement disorders and dementias

The sympathetic nervous system greatly influences cardiovascular physiology, and the importance of cardiac innervation abnormalitiesinthephysiopathologyof variouscardiacdiseases has been emphasised. Cardiac neurotransmission imaging with single-photon-emission computed tomography (SPECT) allows in vivo assessment of the myocardial nervous system. At present, the most commonly used SPECT tracer to assess cardiac neurotransmission is metaiodobenzylguanidine labelled with iodine-123 ( 123 I-MIBG). Cardiac 123 I-MIBG scintigraphy allows autonomic neuropathy to be detected in the early stages of diabetes mellitus. In patients with heart failure, the assessment of cardiac sympathetic activity has important prognostic implications. Targeting neuronal dysfunction with 123 I-MIBG scintigraphy in patients with heart transplantation, ischaemic heart disease, hypertension, diabetes mellitus, heart failure, drug-induced cardiotoxicity and dysautonomias can contribute to early diagnosis, prognostic stratification and appropriate treatment [1]. However, this is not all of the uses for 123 I-MIBG, as an emerging application of this tracer is being pursued for studies in movement disorders.

Automatic and Remote Controlled Ictal SPECT Injection for Seizure Focus Localization by Use of a Commercial Contrast Agent Application Pump

In the presurgical evaluation of patients with partial epilepsy, the ictal single photon emission computed tomography (SPECT) is a useful noninvasive diagnostic tool for seizure focus localization. To achieve optimal SPECT scan quality, ictal tracer injection should be carried out as quickly as possible after the seizure onset and under highest safety conditions possible. Compared to the commonly used manual injection, an automatic administration of the radioactive tracer may provide higher quality standards for this procedure. In this study, therefore, we retrospectively analyzed efficiency and safety of an automatic injection system for ictal SPECT tracer application. Over a 31-month period, 26 patients underwent ictal SPECT by use of an automatic remote-controlled injection pump originally designed for CT-contrast agent application. Various factors were reviewed, including latency of ictal injection, radiation safety parameters, and ictal seizure onset localizing value. Times between seizure onset and tracer injection ranged between 3 and 48 s. In 21 of 26 patients ictal SPECT supported the localization of the epileptogenic focus in the course of the presurgical evaluation. In all cases ictal SPECT tracer injection was performed with a high degree of safety to patients and staff. Ictal SPECT by use of a remote-controlled CT-contrast agent injection system provides a high scan quality and is a safe and confirmatory presurgical evaluation technique in the epilepsy-monitoring unit.

Imaging Onset and Propagation of ECT‐induced Seizures

Regions of seizure onset and propagation in human generalized tonic-clonic seizures are not well understood. Cerebral blood flow (CBF) measurements with single photon emission computed tomography (SPECT) during electroconvulsive therapy (ECT)-induced seizures provide a unique opportunity to investigate seizure onset and propagation under controlled conditions. ECT stimulation induces a typical generalized tonic-clonic seizure, resembling spontaneous generalized seizures in both clinical and electroencephalogram (EEG) manifestations. Patients were divided into two groups based on timing of ictal (during seizure) SPECT tracer injections: 0 s after ECT stimulation (early group), and 30 s after ECT (late group). Statistical parametric mapping (SPM) was used to determine regions of significant CBF changes between ictal and interictal scans on a voxel-by-voxel basis. In the early injection group, we saw increases near the regions of the bitemporal stimulating electrodes as well as some thalamic and basal ganglia activation. With late injections, we observed increases mainly in the parietal and occipital lobes, regions that were quiescent 30 s prior. Significant decreases occurred only at the later injection time, and these were localized to the bilateral cingulate gyrus and left dorsolateral frontal cortex. Activations in distinct regions at the two time points, as well as sparing of intermediary brain structures, suggest that ECT-induced seizures propagate from the site of initiation to other specific brain regions. Further work will be needed to determine if this propagation occurs through cortical-cortical or cortico-thalamo-cortical networks. A better understanding of seizure propagation mechanisms may lead to improved treatments aimed at preventing seizure generalization.

Targeting neuronal dysfunction and receptor imaging

The sympathetic nervous system has great influence on cardiovascular physiology, and the importance of cardiac innervation abnormalities in the physiopathology of various cardiac diseases has been emphasized. Cardiac neurotransmission imaging with single-photon emission computed tomography (SPECT) allows in vivo assessment of the myocardial nervous system. At present, the most commonly used SPECT tracer to assess cardiac neurotransmission is metaiodobenzylguanidine labelled with iodine-123 ((123)I-MIBG). In patients with heart transplantation, ischemic heart disease, dysautonomias and drug-induced cardiotoxicity, assessment of neuronal function can help characterise the disease and improve the prognostic stratification. Cardiac (123)I-MIBG scintigraphy allows autonomic neuropathy to be detected in the early stages of diabetes mellitus. In patients with heart failure, the assessment of cardiac sympathetic activity has important prognostic implications. Future directions in cardiac sympathetic neurotransmission include the development of new tracers, targeting of second-messenger molecules and early assessment of cardiac neurotransmission in genetically predisposed subjects for prevention of heart failure.

Database of normal human cerebral blood flow measured by SPECT: I. Comparison between I-123-IMP, Tc-99m-HMPAO, and Tc-99m-ECD as referred with O-15 labeled water PET and voxel-based morphometry

Three accumulative tracers, iodine-123-labeled N-isopropyl-p-iodoamphetamine (I-123-IMP), technetium-99m-labeled hexamethylpropyleneamineoxime (Tc-99m-HMPAO), and technetium-99m-labeled ethyl cysteinate dimer (Tc-99m-ECD) are widely used to measure cerebral blood flow (CBF) in single-photon emission computed tomography (SPECT). In the present study, normal regional distribution of CBF measured with three different SPECT tracers was entered into a database and compared with regional distribution of CBF measured by positron emission tomography (PET) with H2(15)O. The regional distribution of tissue fractions of gray matter determined by voxel-based morphometry was also compared with SPECT and PET CBF distributions. SPECT studies with I-123-IMP, Tc-99m-HMPAO, and Tc-99m-ECD were performed on 11, 20, and 17 healthy subjects, respectively. PET studies were performed on 11 healthy subjects. Magnetic resonance (MR) imaging studies for voxel-based morphometry were performed on 43 of the 48 subjects who underwent SPECT study. All SPECT, PET, and MR images were transformed into the standard brain format with the SPM2 system. The voxel values of each SPECT and PET image were globally normalized to 50 ml/100 ml/min. Gray matter, white matter, and cerebrospinal fluid images were segmented and extracted from all transformed MR images by applying voxel-based morphometry methods with the SPM2 system. Regional distribution of all three SPECT tracers differed from that of H2150 in the pons, midbrain, thalamus, putamen, parahippocampal gyrus, posterior cingulate gyrus, temporal cortex, and occipital cortex. No significant correlations were observed between the tissue fraction of gray matter and CBF with any tracer. Differences in regional distribution of SPECT tracers were considered to be caused mainly by differences in the mechanism of retention of tracers in the brain. Regional distribution of CBF was independent of regional distribution of gray matter fractions, and consequently the blood flow per gray matter volume differed for each brain region.

Molecular Beacons Illuminate Subcellular Events

Building on decades of technological advances and imaging experience, during which noninvasive imaging of cardiac structure and function, myocardial perfusion and viability, and noncoronary vascular pathology have become intimately entwined in routine clinical practice, advanced imaging techniques are now poised to deliver noninvasive coronary arteriograms and to delineate the coronary artery wall in exquisite detail. At the same time that these highly promising methods for anatomic imaging at the macroscopic level are creating great excitement among physicians, their patients, and the public, a quieter imaging revolution is underway with steady progress in detecting and tracking fundamental biological processes at the cellular and subcellular levels. In the era of genomic research, molecular biology, and stem cell therapies, these methods have great potential to accelerate understanding of basic pathophysiological processes in animals and humans and to develop new tools for early diagnosis and drug development. Cardiovascular molecular imaging is taking hold. See p 1800 Molecular imaging is the science of visually representing, characterizing, and quantifying cellular/subcellular biological processes in intact organisms. These processes include gene expression, protein–protein interaction, signal transduction, cellular metabolism, and both intracellular and intercellular trafficking. Molecular imaging has the potential to quantify these events, to monitor multiple events simultaneously, to localize these events in 3 dimensions, and to monitor these events serially. Thus, biological processes can be identified and studied in time and space, providing “4-dimensional” information. The emergence of molecular imaging has coincided with and has been made possible by the enormous progress in molecular biology, cell biology, and transgenic animal models, as well as the development of imaging probes that are specific, reproducible, and quantifiable.1 Molecular imaging was once the sole domain of nuclear medicine, with tracers developed for both positron emission tomography (PET) and single photon emission computed tomography (SPECT). Examples include antimyosin antibodies for …

Cardiac neurotransmission SPECT imaging

The sympathetic nervous system has great influence on cardiovascular physiology. Cardiac neurotransmission single photon emission computed tomography (SPECT) imaging allows in vivo noninvasive assessment of presynaptic reuptake and storage of neurotransmitters, which offers characterization of the cardiac neuronal function in different diseases of the heart and other altered metabolic or functional conditions. Therefore assessment of the integrity of cardiac sympathetic innervation may help in the diagnosis of these disorders, as well as in prognostication, and will result in better therapy and outcome. At present, the most widely available SPECT tracer by which to assess cardiac neurotransmission is metaiodobenzylguanidine labeled with iodine 123. This article focuses on reviewing the characteristics of cardiac SPECT imaging with I-123 metaiodobenzylguanidine and its role in the assessment of pathophysiologic changes during relevant clinical conditions.

Determination of lipophilicity and its use as a predictor of blood–brain barrier penetration of molecular imaging agents

Compound lipophilicity is a fundamental physicochemical property that plays a pivotal role in the absorption, distribution, metabolism, and elimination (ADME) of therapeutic drugs. Lipophilicity is expressed in several different ways, including terms such as Log P, clogP, delta Log P, and Log D. Often a parabolic relationship exists between measured lipophilicity and in vivo brain penetration of drugs, where those moderate in lipophilicity often exhibit highest uptake. Reduced brain extraction of more lipophilic compounds is associated with increased non-specific binding to plasma proteins. More lipophilic compounds can also be more vulnerable to P450 metabolism, leading to faster clearance. Very polar compounds normally exhibit high water solubility, fast clearance through the kidneys, and often contain ionizable functional groups that limit blood–brain barrier (BBB) penetration. The brain penetration and specific to non-specific binding ratios exhibited in vivo by positron emission tomography (PET) and single photon emission computed tomography (SPECT) radiotracers involves a complex interplay between many critical factors, including lipophilicity, receptor affinity, metabolism, molecular size and shape, ionization potential, and specific binding to BBB efflux pumps or binding sites on albumin or other plasma proteins. This paper explores situations in which lipophilicity is a good predictor of BBB penetration, as well as those where this correlation is poor. The more commonly used methods for measuring lipophilicity are presented, and the various terms often found in the literature outlined. An attempt is made to describe how this information can be used in optimizing the development of PET and SPECT tracers that target the central nervous system (CNS).

SPECT imaging of dopamine and serotonin transporters with [123I]β‐CIT: Pharmacological characterization of brain uptake in nonhuman primates

Single photon emission computed tomography (SPECT) studies of regional kinetic uptake and pharmacological specificity of [123I]methyl 3 beta-(4-iodophenyl) tropane-2 beta-carboxylate ([123I]beta-CIT) were performed in nonhuman primates (n = 41). In control experiments, activity was concentrated in striatum and in hypothalamic/midbrain regions. Striatal uptake increased for 140-180 min and displayed stable levels thereafter. Striatal to cerebellar activity ratios were 7.3 +/- 0.9 (mean +/- SEM) at 300 min. About 75% of striatal uptake was displaceable by injection of nonradioactive beta-CIT. Hypothalamic/midbrain activity reached maximal levels at approximately 45 min. A slow washout phase followed this peak activity. Activities in frontal, occipital, and cerebellar regions were characterized by an early peak (20-30 min), followed by rapid washout. Displacement studies demonstrated that striatal uptake was associated with dopamine (DA) transporters, as it was displaced by GBR 12909, a selective DA uptake inhibitor, but not by citalopram, a selective serotonin (5-HT) uptake inhibitor. The inverse was true in the hypothalamic/midbrain area, suggesting that the uptake in this area was associated primarily with 5-HT transporters. Maprotiline, a selective norepinephrine uptake inhibitor, did not affect [123I]beta-CIT uptake. In vivo site occupancy ED50 values of cocaine, 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT), and beta-CIT were measured in the striatum with a stepwise displacement paradigm. In vivo ED50 values correlated strongly with in vitro IC50 values for binding to DA transporters. Infusion of high dose of L-DOPA (250 mumol/kg) failed to displace striatal [123I]beta-CIT binding, suggesting that the binding would not be affected by L-DOPA administration in Parkinsonian patients. However, studies performed with injection of d-amphetamine indirectly suggested that high synaptic levels of DA may compete with [123I]beta-CIT binding. These studies suggest that [123I]beta-CIT will be a useful SPECT tracer of DA and 5-HT transporters in living human brain.