Modulation of amphetamine-induced striatal dopamine release by ketamine in humans: implications for schizophrenia.

BACKGROUND: Recent brain imaging studies have indicated that schizophrenia is associated with increased amphetamine-induced dopamine release in the striatum. It has long been hypothesized that dysregulation of subcortical dopamine systems in schizophrenia might result from a failure of the prefrontal cortex (PFC) to adequately control subcortical dopaminergic function. The activity of midbrain dopaminergic neurons is regulated, in part, by glutamatergic projections from the PFC acting via glutamatergic N-methyl-D-aspartate (NMDA) receptors. The goal of this study was to test the hypothesis that a pharmacologically induced disruption of NMDA transmission leads to an increase in amphetamine-induced dopamine release in humans. METHODS: In eight healthy volunteers, we compared striatal amphetamine-induced (0.25 mg/kg) dopamine release under control conditions and under sustained disruption of NMDA transmission induced by infusion of the noncompetitive NMDA antagonist ketamine (0.2 mg/kg intravenous bolus followed by 0.4 mg/kg/hour intravenous infusion for 4 hours). Amphetamine-induced dopamine release was determined with single photon emission computed tomography, as the reduction in the binding potential (BP) of the radiolabeled D(2) receptor antagonist [(123)I]IBZM. RESULTS: Ketamine significantly enhanced the amphetamine-induced decrease in [(123)I]IBZM BP, from -5.5% +/- 3.5% under control conditions to -12. 8% +/- 8.8% under ketamine pretreatment (repeated-measures analysis of variance, p =.023). CONCLUSIONS: The increase in amphetamine-induced dopamine release induced by ketamine (greater than twofold) was comparable in magnitude to the exaggerated response seen in patients with schizophrenia. These data are consistent with the hypothesis that the alteration of dopamine release revealed by amphetamine challenge in schizophrenia results from a disruption of glutamatergic neuronal systems regulating dopaminergic cell activity.

Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression.

BACKGROUND: Reduced dopaminergic transmission has been implicated in the pathophysiology of major depression. The aim of the present study was to measure striatal D(2) receptor availability and amphetamine-induced dopamine release in nonpsychotic, unmedicated, unipolar patients during an episode of major depression. METHODS: The striatal equilibrium specific to nonspecific partition coefficient (V(3)") of the D(2) receptor antagonist [(123)I]IBZM was measured with single photon emission computerized tomography before and after amphetamine administration in 9 depressed subjects and 10 matched healthy control subjects. RESULTS: No significant differences were observed in preamphetamine D(2) receptor availability between depressed patients (0.73 +/- 0.08) and control subjects (0.78 +/- 0.10, p =.23). Amphetamine-induced reduction in [(123)I]IBZM V(3)" (DeltaV(3)") was similar in depressed patients (-9.8 +/- 5.5%) and control subjects (-7.8 +/- 2.5%, p =.32). Amphetamine induced a transient improvement in symptomatology in depressed patients, but this improvement did not correlate with [(123)I]IBZM DeltaV(3)". CONCLUSIONS: This study did not replicate previously reported alterations in striatal D(2) receptor density in depressed patients and suggests that stimulant-induced dopamine release is not altered in major depression.

Graphical, kinetic, and equilibrium analyses of in vivo [123I] beta-CIT binding to dopamine transporters in healthy human subjects.

The in vivo kinetics of the dopamine (DA) transporter probe 123I-labeled 2 beta-carboxymethoxy-3 beta-(4-iodophenyl) tropane ([123I] beta-CIT) in striatum was investigated with single-photon emission computerized tomography (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 regional 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 measure the input function. Graphical, kinetic, and equilibrium 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 > 0)-parameter model. The three-parameter model estimated the konBmax product at 0.886 +/- 0.087 min-1. The four-parameter model gave a binding potential (BP) of 476 ml g-1, a value consistent with in vitro measurements. The stability of the regional uptake on day 2 allowed direct measurement of the specific to nonspecific equilibrium partition coefficient (V3" = k3/k4 = 6.66 +/- 1.54). Results of day 1 kinetic analysis and day 2 equilibrium 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 equilibrium 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.

SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates: I. Kinetic modeling of single bolus experiments.

The aim of this work was to study the feasibility and reproducibility of in vivo measurement of benzodiazepine receptors with single photon emission computerized tomography (SPECT) in the baboon brain. Arterial and brain regional activities were measured for 420 min in three baboons after single bolus injection of the benzodiazepine antagonist [123I]iomazenil. Data were fit to a three-compartment model to derive the regional binding potential (BP), which corresponds to the product of the receptor density, (Bmax) and affinity (1/KD). Regional BP values (from 114 in striatum to 241 in occipital) were in good agreement with values predicted from in vitro studies. Constraining the regional volume of distribution of the nondisplaceable compartment to the value measured during tracer constant infusion experiments in baboons (Laruelle et al., 1993) improved the identifiability of the rate constants. Each experiment was repeated to investigate the reproducibility of the measurement. The regional average reproducibility was 10 +/- 5%, expressed as coefficient of variation (CV). Results of equilibrium analysis at peak uptake were in good agreement with results of kinetic analysis. Empirical counts ratio methods were found to be poorly sensitive to benzodiazepine receptor density. These studies suggest the feasibility of quantitative measurement of benzodiazepine receptors by kinetic analysis of SPECT data and the inadequacy of empirical methods of analysis, such as counts ratios, to evaluate differences in receptor density.

SPECT quantification of [123I]iomazenil binding to benzodiazepine receptors in nonhuman primates: II. Equilibrium analysis of constant infusion experiments and correlation with in vitro parameters.

In vivo benzodiazepine receptor equilibrium dissociation constant, KD, and maximum number of binding sites, Bmax, were measured by single photon emission computerized tomography (SPECT) in three baboons. Animals were injected with a bolus followed by a constant i.v. infusion of the high affinity benzodiazepine ligand [123I]iomazenil. Plasma steady-state concentration and receptor-ligand equilibrium were reached within 2 and 3 h, respectively, and were sustained for the duration (4-9 h) of the experiments (n = 15). At the end of the experiments, a receptor saturating dose of flumazenil (0.2 mg/kg) was injected to measure nondisplaceable activity. Experiments were carried out at various levels of specific activity, and Scatchard analysis was performed for derivation of the KD (0.59 +/- 0.09 nM) and Bmax (from 126 nM in the occipital region to 68 nM in the striatum). Two animals were killed and [125I]iomazenil Bmax and KD were measured at 22 and 37 degrees C on occipital homogenate membranes. In vitro values of Bmax (114 +/- 33 nM) and 37 degrees C KD (0.66 +/- 0.16 nM) were in good agreement with in vivo values measured by SPECT. This study demonstrates that SPECT can be used to quantify central neuroreceptors density and affinity.

Low dopamine D(2) receptor binding potential in social phobia.

OBJECTIVE: This study compared dopamine D(2) receptor binding potential in patients with social phobia and healthy comparison subjects. METHOD: Dopamine D(2) receptor binding potential was assessed in 10 unmedicated subjects with generalized social phobia and no significant lifetime psychiatric comorbidity and 10 healthy comparison subjects matched for age and sex. Binding potential was measured in the striatum by using single photon emission computerized tomography and constant infusion of the D(2) receptor radiotracer [(123)I]iodobenzamide ([(123)I]IBZM). RESULTS: Mean D(2) receptor binding potential was significantly lower in the subjects with social phobia than in the comparison subjects. Within the social phobia group, there was a nonsignificant correlation of binding potential with the Liebowitz Social Anxiety Scale score. CONCLUSIONS: Generalized social phobia may be associated with low binding of [(123)I]IBZM to D(2) receptors in the striatum.

[123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease.

We have used in vivo single-photon emission computed tomography (SPECT) of the dopamine transporter with 2 beta-carboxymethoxy-3 beta-(4-iodophenyl)tropane ([123I] beta-CIT) to investigate striatal dopamine transporter loss in patients with early Parkinson's disease (PD). Striatal uptake of ([123I] beta-CIT was compared in eight early-PD patients with exclusively hemi-parkinsonism and eight age- and sex-matched healthy subjects. [123I] beta-CIT striatal uptake was reduced by approximately 53% contralateral and by 38% ipsilateral to the clinically symptomatic side in the hemi-PD patients, compared with the mean striatal uptake in age- and sex-matched healthy subjects. The relative reduction in [123I] beta-CIT uptake in the hemi-PD patients was greater in the putamen than in the caudate. These data demonstrate that SPECT imaging of the dopamine transporter with [123I] beta-CIT can identify patients with PD at the onset of motor symptoms and suggest that this technique also may be useful in identifying individuals with developing dopaminergic pathology before onset of motor symptoms.

[123I]iomazenil SPECT imaging demonstrates significant benzodiazepine receptor reserve in human and nonhuman primate brain.

SPECT imaging with [123I]iomazenil was used to measure benzodiazepine (BZ) neuroreceptor occupancy of the agonist lorazepam administered at therapeutically relevant doses in humans and supratherapeutic doses in monkeys. Lorazepam at therapeutic doses (0.03 mg/kg, i.v.) administered 90 min after the bolus injection of [123I]iomazenil had no statistically significant effect (P > 0.12) on the washout rates of regional brain activities compared to that in control subjects, although human subjects demonstrated marked sedation from the lorazepam. In baboons, the effects of higher doses of lorazepam (cumulative 0.5 mg/kg) were examined in a stepwise displacement paradigm. The in vivo potency was expressed as the ED50 (or dose required to displace 50% of receptor bound activity) and was equal to 0.34 +/- 0.01 mg/kg (mean +/- SD, n = 12). Log-logit analyses of displacement data corrected for endogenous washout showed that therapeutic doses of lorazepam were associated with < 3% BZ receptor occupancy. To examine if endogenous GABA modulates potency of the BZ agonist, the ED50 of lorazepam was compared with and without concurrent administration of tiagabine, a GABA reuptake inhibitor. These experiments were designed to measure an in vivo GABA shift of agonist potency. In vivo microdialysis demonstrated that tiagabine (up to 1 mg/kg, i.v.) increased extracellular GABA levels up to 200% of baseline, but these doses had only a minimal enhancement of lorazepam's potency to displace [123I]iomazenil. This study strongly suggests that single therapeutically relevant doses of lorazepam occupy a relatively small percentage (i.e. < 3%) of BZ receptors and that BZ binding sites have a significant (i.e. > 97%) receptor reserve.

Preparation and evaluation of radioiodinated (iodophenyl)cholines and their morpholinium and piperidinium analogues as myocardial perfusion imaging agents.

A series of nine radioiodinated quaternary ammonium salts related to phenylcholine were synthesized, characterized, and radiolabeled by exchange. These compounds were evaluated as myocardial perfusion imaging agents in mice, pigs, and humans. Mice biodistribution studies showed that five of the nine compounds were taken up in the heart to the same extent as 201Tl+ at 5 min. At 60 min myocardial retention was significantly better than 201Tl+ for six of the compounds. Several of the compounds showed more favorable heart/blood and heart/liver ratios when compared to 201Tl+. Evaluation of three of the more promising compounds in pigs and humans however revealed no selective myocardial uptake.

Simplified multidose preparation of iodine-123-beta-CIT: a marker for dopamine transporters.

UNLABELLED: Iodine-123-beta-CIT is a SPECT radioligand for dopamine and 5-HT transporters with potential use in Parkinson's disease, schizophrenia and cocaine addiction studies. At present, preparation of no-carrier-added (NCA) [123I] beta-CIT is achieved by iododestannylation of a trialkylstannyl precursor with sodium [123I]iodide in the presence of oxidizing agent, followed by preparative HPLC. The purpose of this study was to develop a faster and simpler method for the routine preparation of this radiopharmaceutical. METHODS: Purification of the labeled compound was accomplished by solid phase extraction (SPE) with a C-18 Sep-Pak Light cartridge, which removed unreacted iodide, reaction reagents, polar side products and tributylstannyl precursor. The tributylstannyl precursor was preferred as starting material over the trimethylstannyl precursor due to its higher lipophilicity, allowing better separation of the labeled product and precursor. A TLC method was developed to assess the radiochemical purity of the final product. RESULTS: The method produced [123I] beta-CIT in high radiochemical yields (75% +/- 4%), with high radiochemical purity (> or = 98%) and specific activity (> 67000 Ci/mmole), in 1.5 hr. The final formulation was sterile and pyrogen free. CONCLUSION: The results obtained by solid phase extraction are consistent with those obtained by the HPLC method; with the advantage that the SPE method does not require solvent extraction, evaporation under reduced pressure or HPLC purification.

Reproducibility of SPECT measurement of benzodiazepine receptors in human brain with iodine-123-iomazenil.

UNLABELLED: Iodine-123-iomazenil is a SPECT radiotracer used to image and quantify benzodiazepine receptors. The reproducibility of the measurement of benzodiazepine receptors in human brain with [123I]iomazenil and SPECT was investigated with a test/retest paradigm. METHODS: Six subjects underwent two experiments during a 1-wk interval. Iodine-123-iomazenil was injected as a single bolus (12 mCi). The time-activity curves of the tracer in the arterial plasma were measured and corrected for metabolites. Regional time-activity curves of five brain regions were measured with the CERASPECT camera for 145 min postinjection with serial 2-min acquisitions. Data were analyzed using three kinetic models that included a two-compartment model, an unconstrained three-compartment model and a three-compartment model with a constraint on the nondisplaceable compartment. RESULTS: The results from the various analyses and fitting strategies were compared. The variability (average absolute difference between test and retest, expressed as a percentage of the mean of both measurements) was 10% to 17%, depending on the outcome measure and the fitting procedure. The most reproducible outcome measure was the regional tracer distribution volume relative to the total arterial concentration (VT'). VT' showed an average regional variability of 10% +/- 2%, with an intraclass correlation coefficient of 0.81. CONCLUSION: SPECT measurement of regional [123I]iomazenil VT' is reproducible and reliable. The use of regional ratios results in a significant loss of information.

Age-related decline in striatal dopamine transporter binding with iodine-123-beta-CITSPECT.

UNLABELLED: The effect of age on human striatal dopamine (DA) transporters was investigated with SPECT using the ligand [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT). METHODS: Iodine-123-beta-CIT binding in the striatum was examined in 28 healthy human subjects (14 men, 14 women) who ranged in age from 18 to 83 yr. Following injection with [123I]beta-CIT (mean +/- s.d. = 9.9 +/- 1.2 mCi), subjects were scanned with the brain-dedicated CERASPECT camera. A reconstructed transaxial slice 13.3-mm thick at the level of maximal striatal activity was used to determine tracer uptake in striatal and occipital regions of interest. The stability of regional uptake on Day 2 (approximately 18-24 hr postinjection) permitted estimation of the specific-to-nondisplaceable equilibrium partition coefficient: V3", calculated as (striatal--occipital)/occipital uptake at equilibrium. RESULTS: Values of V3" ranged from 3.6 to 11.4 for this sample (6.7 +/- 1.9). V3" showed a significant inverse correlation with age (r = -0.73, n = 28, p < 0.0001). Linear regression analysis revealed that V3" declined by 51% over the age range studied or approximately 8% per decade. CONCLUSION: These findings confirm postmortem reports of dopamine transporter loss with aging. In vivo methodologies may permit the age-related degeneration of dopamine nerve terminals to be studied in relation to the cognitive and motor deficits that occur in normal aging.

SPECT imaging of striatal dopamine release after amphetamine challenge.

UNLABELLED: This study assesses the feasibility of using SPECT to image intrasynaptic dopamine release in human striatum following dextroamphetamine sulfate (d-amphetamine) challenge testing. METHODS: A bolus plus constant infusion administration schedule of the D2 receptor radiotracer [123I]iodobenzamide ([123I]IBZM) was used to obtain a stable baseline for reliable quantitation of the d-amphetamine effect. Eight healthy subjects first underwent a controlled experiment to demonstrate that stable levels of striatal and occipital activities could be maintained from 150 to 420 min during programmed infusion of the tracer. Next, seven subjects underwent the experiment with d-amphetamine. The experimental conditions were identical except that 0.3 mg/kg amphetamine was injected intravenously at 240 min. The behavioral effects of d-amphetamine were measured by self-rating on the following analog scales: euphoria, alertness, restlessness and anxiety. RESULTS: The d-amphetamine injection induced a 15% +/- 4% (mean +/- s.d.) decrease in D2 receptor availability, measured as the specific-to-nonspecific equilibrium partition coefficient (V3"). The d-amphetamine injection induced marked increase in euphoria, alertness and restlessness scores. The intensity of these behavioral responses correlated with the decrease in D2 availability measured with SPECT. In contrast, the anxiety response was milder and not correlated with the decrease in D2 availability. CONCLUSION: These studies demonstrate the feasibility of using [123I]IBZM programmed infusion and SPECT imaging to measure endogenous dopamine release after d-amphetamine challenge and to study brain neurochemical correlates of emotions.

Continuous intravenous infusion of iodine-123-IBZM for SPECT determination of human brain dopamine receptor occupancy by antipsychotic agent RWJ-37796.

UNLABELLED: PET has shown that dose-dependent in vivo occupancy of dopamine receptors by antipsychotic drugs is associated with clinical response to antipsychotic agents and the production of extrapyramidal side effects. We studied the feasibility of administering [123I]IBZM as a bolus plus continuous infusion over 8 hr to achieve unchanging regional brain activity levels, and the application of [123I]IBZM continuous infusion to examine the effects of the antipsychotic agent RWJ-37796, on striatal activity in humans. METHODS: Five healthy male subjects received a bolus of [123I]IBZM followed by a continuous infusion at a bolus (mCi):infusion (mCi/hr) ratio of 6:1. Serial SPECT images were obtained every 2-3 min for a total of 8 hr with a 1-2 hr break in the scanning session. Serial venous blood samples were obtained every 30 min for the duration of the study. All five subjects achieved unchanging plasma [123I]IBZM and striatal brain-activity levels over the 300-420 min postinitiation of tracer infusion. Two subjects achieved flat brain time-activity curves later than the others, suggesting the bolus-to-infusion ratio was slightly high. An additional six healthy male subjects received a similar bolus plus constant infusion of [123I]IBZM. RWJ-37796 (0.04 mg/kg) was administered intravenously 157 +/- 13.7 min after the initiation of [123I]IBZM infusion. Serial SPECT brain images, serum prolactin and extrapyramidal side effect ratings were obtained for an additional 330 min. RESULTS: All six subjects demonstrated rapid and marked reduction of striatal activity following RWJ-37796 without return of striatal activity to baseline levels over the 5.5 hr of continued [123I]IBZM administration. Estimated receptor occupancy by RWJ-37796 was 57% +/- 5% (range 47%-67%). Prolactin was only transiently increased in all subjects by 1054% +/- 1084% over baseline. One subject experienced moderate extrapyramidal symptoms (akasthisia) during RWJ-37796 injection. CONCLUSION: SPECT imaging during continuous [123I]IBZM infusion provides a powerful within-scan method for determining both temporal binding characteristics and receptor occupancy of striatal dopamine receptors by antipsychotic agents.

Reproducibility of iodine-123-beta-CIT SPECT brain measurement of dopamine transporters.

UNLABELLED: Iodine-123-beta-CIT has been used as a probe of monoamine transporters in human and nonhuman primates utilizing SPECT. To assess the utility of this tracer for measurement of striatal dopamine (DA) transporters in human disease, we studied the test/retest variability and reliability of SPECT measures obtained after bolus injection of [123I]beta-CIT 0-7 hr (Day 1) and 18-24 hr (Day 2) after administration. METHODS: For the Day 2 study, seven healthy humans (4 men, 3 women; aged 19-74 yr) participated in two [123I]beta-CIT SPECT scans separated by 7-14 days. Subjects were imaged at 18, 21 and 24 hr postinjection of 370 MBq (10 mCi) [123I]beta-CIT. Two outcome measures were evaluated: (a) the ratio of specific striatal (activity associated with DA transporter binding) to nondisplaceable uptake, also designated V"3 and (b) the total, specific striatal uptake (%SSU) expressed as a percentage of injected radiotracer dose. Test/retest variability associated with V"3 and total specific striatal uptakes were compared for scans acquired at 18, 21 and 24 hr with 24 hr only postinjection scans. For the Day 1 study, three of the subjects participated in two kinetic studies of [123I]beta-CIT uptake. A three-compartment model was used for determination of konBmax and binding potential (BP = Bmax/Kd) and the reproducibility of the measures assessed. RESULTS: In the Day 2 study, both outcome measures demonstrated excellent test/retest reproducibility with variability of V"3 = 6.8 +/- 6.8% and percent striatal uptake = 6.6 +/- 4.3% using data acquired from all time points. There were no significant differences in variability for the two outcome measures obtained. The intraclass correlation coefficient rho was 0.96 and 0.98 for V"3 and %SSU, respectively. Considering the 24 hr postinjection scans only, there was a nonsignificant trend toward lower test/retest variability for %SSU compared to V"3 (6.6 +/- 4.2% and 12.8 +/- 9.0%, respectively). The test/retest variability for the Day 1 kinetic modeling data showed marked differences depending on the fitting strategy and assumptions about the reversibility of [123I]beta-CIT in striatum. Using a model that assumed a low, fixed value for reversible striatal binding (k4) produced low variability (12 +/- 9%). CONCLUSION: These data suggest that SPECT imaging performed at either 0-7 hr or 18-24 hr after [123I]beta-CIT injection permits calculation of reliable and reproducible measures of dopamine transporters and supports the feasibility of using [123I]beta-CIT in serial evaluation of human neuropsychiatric disease.

Human biodistribution and dosimetry of the SPECT benzodiazepine receptor radioligand iodine-123-iomazenil.

UNLABELLED: SPECT imaging of the brain with [123I]iomazenil has shown avid uptake of the radioligand in a distribution consistent with benzodiazepine receptor binding. The purposes of this study were to measure the whole-body distribution of activity following i.v. administration of [123I]iomazenil and to evaluate the resulting organ radiation burdens. METHODS: Serial total body scans were obtained in healthy volunteers after thyroid blockade and demonstrated avid brain uptake of radioligand. RESULTS: Abdominal imaging showed significant activity retention within the urinary and gastrointestinal tracts consistent with excretion via these routes. Absorbed dose to the urinary bladder was calculated to be 0.19 mGy/MBq, to the lower large intestine 0.079 mGy/MBq, to the upper large intestine 0.066 mGy/MBq, and to the thyroid 0.063 mGy/MBq. CONCLUSION: Thyroid uptake may in part have represented binding to benzodiazepine receptors, since radioligand binding to tissue homogenates prepared from human thyroid showed the presence of benzodiazepine binding sites.

Compartmental modeling of iodine-123-iodobenzofuran binding to dopamine D2 receptors in healthy subjects.

UNLABELLED: Iodine-123-labeled iodobenzofuran ([123I]IBF) is a potent dopamine D2 antagonist that provides good visualization of D2 receptors in primates. METHODS: The feasibility of measuring dopamine D2 binding potential with [123I]IBF in humans was evaluated in eight healthy subjects. Following [123I]IBF injection (6 mCi), scans were acquired every 10 min for 160 min with the brain-dedicated CERASPECT camera. Arterial activities were obtained at various intervals and corrected for the presence of metabolites by extraction followed by reverse-phase high-performance liquid chromatography. RESULTS: Reconstructed images exhibited adequate basal ganglia-to-occipital ratios (from 1.96 +/- 0.34 at 30 min to 3.54 +/- 0.71 at 150 min, mean +/- s.d.). Time-activity curves demonstrated reversibility, with peak basal ganglia uptake at 50 +/- 25 min. Regional time-activity curves were analyzed with kinetic three-compartment modeling and graphic analysis. In all subjects, D2 binding potential values, as derived by both methods, were in excellent agreement (mean +/- s.d. D2 binding potential = 129 +/- 51). An empiric count ratio method that does not require measurement of arterial tracer concentrations was evaluated and found to be in reasonable agreement with the model-derived binding potential. CONCLUSION: Iodine-131-IBF is a suitable ligand for quantitative studies of D2 receptor density with SPECT in humans.

Whole-body biodistribution, radiation absorbed dose and brain SPECT imaging with iodine-123-beta-CIT in healthy human subjects.

UNLABELLED: SPECT imaging with 123I-labeled methyl 3 beta-(4-iodophenyl)tropane-2 beta-carboxylate ([123I]beta-CIT) in nonhuman primates has shown brain striatal activity, which primarily reflects binding to the dopamine transporter. The biodistribution and calculated radiation-absorbed doses of [123I]beta-CIT administered to eight healthy subjects were measured with attention to the accurate determination of organ time-activity data. METHODS: Whole-body transmission images were obtained with a scanning line source for attenuation correction of the emission images. Following administration of 92.5 +/- 22.2 MBq (2.5 +/- 0.6 mCi) of [123I]beta-CIT, subjects were imaged with a whole-body imager every 30 min for 3 hr, every 60 min for the next 3 hr and at 12, 24 and 48 hr postinjection. Regional body conjugate counts were converted to microcuries of activity, with a calibration factor determined in a separate experiment using a distributed source of 123I. RESULTS: The peak brain uptake represented 14% of the injected dose, with 2% of the activity approximately overlying the striatal region. Highest radiation-absorbed doses were to the lung (0.1 mGy/MBq, 0.38 rads/mCi), liver (0.087 mGy/MBq, 0.32 rads/mCi) and lower large intestine (0.053 mGy/MBq, 0.20 rads/mCi). CONCLUSIONS: Iodine-123-beta-CIT is a promising SPECT agent for imaging of the dopamine transporter in humans with favorable dosimetry and high brain uptake.

Dynamic SPECT imaging of dopamine D2 receptors in human subjects with iodine-123-IBZM.

We studied the uptake, distribution, metabolism and washout of the dopamine D2 receptor ligand [123I]IBZM in healthy subjects (n = 12) with dynamic brain SPECT. The highest radioactivity level was detected in the striatum. Operationally-defined striatal "specific" uptake peaked at 69 min postinjection of radioligand and showed a gradual decline of 15% per hour thereafter. "Specific" uptake at maximal counts represented 53% of the total striatal radioactivity. Two subjects received haloperidol (20 micrograms/kg i.v.) 80 min postinjection of radioligand. Haloperidol caused a 2.6-fold increase in the rate of washout of specific striatal activity in comparison to that in the 10 control subjects and was consistent with drug-induced displacement of radioligand from the dopamine D2 receptor. Two classes of metabolites were detected in plasma and urine: a polar fraction, not extracted by ethyl acetate, and a nonpolar, extractable fraction consisting of parent compound and two compounds having shorter retention times on reversed-phase HPLC. Greater than half the plasma parent was metabolized within 10-15 min after administration. The volume of distribution, estimated from the peak arterial plasma concentration at 50-75 sec, was 7.7-10.2 l; the free (nonprotein bound) fraction of [123I]IBZM after in vitro incubation with blood or plasma was 4.4% +/- 0.4%. These results suggest that [123I]IBZM exhibits uptake in brain regions with high D2 receptor density and shows a relatively stable washout during which drugs affecting dopaminergic transmission may be administered.

Test/retest reproducibility of iodine-123-betaCIT SPECT brain measurement of dopamine transporters in Parkinson's patients.

UNLABELLED: Iodine-123-beta-CIT has been used as a probe of dopamine transporters in Parkinson's disease patients using SPECT. We studied the test/retest reproducibility of SPECT measures in Parkinson's disease patients and healthy controls obtained after injection of [123I])beta-CIT in part to assess the utility of this tracer for longitudinal evaluation of striatal dopamine transporters as a marker of disease progression. METHODS: Seven Parkinson's disease patients and seven healthy control subjects participated in two [123I]beta-CIT SPECT scans separated by 7-21 days. Subjects were imaged at 24 hr post injection of 360 MBq (9.7 mCi) of [123I]beta-CIT. Two outcome measures were evaluated; 1) the ratio of specific striatal (activity associated with DA transporter binding) to nondisplaceable uptake, also designated V3," and 2) the total specific striatal uptake (%SSU) expressed as a percentage of injected radiotracer dose. For both measures, test/retest variability was calculated as the absolute difference of test minus retest divided by the mean of test/retest and expressed as a percent. In addition, the reproducibility of left and right striatal asymmetry and putamen:caudate ratios were determined. RESULTS: The two outcome measures demonstrated excellent test/retest reproducibility for both the Parkinson's disease and healthy subject groups with variability of striatal V3" = 16.8 +/- 13.3% and percent striatal uptake = 6.8 +/- 3.4% for Parkinson's disease patients and V3" = 12.8 +/- 8.9% and %SSU = 7.0 +/- 3.9% for control subjects. There were no statistically significant differences in test/retest variability between control subjects and Parkinson's disease patients for either outcome measure. The reproducibility of left/right asymmetry indices and putamen-to-caudate ratios showed no patient versus control subject differences. The asymmetry index had greater test/retest variability than the other outcome measures. CONCLUSION: These data suggest that SPECT imaging performed at 24 hr postinjection of [123I]beta-CIT permits calculation of reliable and reproducible measures of dopamine transporters in both Parkinson's disease patients and control subjects and supports the feasibility of using [123I]beta-CIT in the evaluation of disease progression in Parkinson's disease.