Serotonin transporter availability may moderate the association between perceiving stress and depressive tendencies - A SPECT with 5-HTTLPR genotyping study.

It was found that serotonin transporter (SERT) gene (5-HTTLPR) polymorphism may moderate the association between perceiving stress and depressive tendency. Although SERT availability in the central nervous system could be associated with 5-HTTLPR polymorphism, whether SERT availability moderates the association between stress and depressive tendency is unclear. This study aimed to investigate whether there is a SERT availability×environmental stress interaction effect, as well as a gene-by-environmental (G×E) interaction effect, using single-photon emission computed tomography (SPECT) with a serotonin transporter radiotracer, [(123)I]ADAM. 87 healthy volunteers were enrolled. The SERT availability was approximated using SPECT with [(123)I]ADAM. Stress and depressive tendencies were measured by the Recent Life Change Questionnaire (RLCQ) and the Taiwanese Depression Questionnaire (TDQ), respectively. A significant interaction of sex×RLCQ×thalamic SERT availability on the TDQ was found, and this effect was robust after controlling for the effect of the SS genotype. The interaction of RLCQ×thalamic SERT availability on the TDQ was significant among males. In particular, a significant association between RLCQ and TDQ (Spearman correlation, ρ=0.64, p<0.01) was found among male subjects with a lower level of thalamic SERT availability. SERT availability may play a role in depressive tendency when under perceived stress among healthy individuals, independent of G×E. This finding provides new evidence that confirms the role of the serotonergic system in the association between stress and depression. Males with lower levels of SERT availability may be more vulnerable to the effects of negative life events.

Small-animal single-photon emission computed tomographic imaging of the brain serotoninergic systems in wild-type and mdr1a knockout rats.

The pharmacokinetic properties of radiotracers are crucial for successful in vivo single-photon emission computed tomographic (SPECT) imaging. Our goal was to determine if MDR1A-deficient animals could allow better SPECT imaging outcomes than wild-type (WT) animals for a selection of serotoninergic radioligands. Thus, we compared the performances of 123I-p-MPPI, 123I-R91150, 123I-SB207710, and 123I-ADAM radioligands, for imaging of their respective targets (5-hydroxytryptamine [5-HT]1A, 5-HT2A, 5-HT4, and serotonin transporter [SERT]), in WT and Mdr1a knockout (KO) rats. With 123I-SB207710, virtually no SPECT signal was recorded in the brain of WT or KO animals. For 123I-p-MPPI, low nondisplaceable binding potentials (BPND, mean ± SD) were observed in WT (0.49 ± 0.25) and KO (0.89 ± 0.52) animals. For 123I-ADAM, modest imaging contrast was observed in WT (1.27 ± 0.02) and KO (1.31 ± 0.09) animals. For 123I-R91150, the BPND were significantly higher in Mdr1a KO (3.98 ± 0.65) animals compared to WT animals (1.22 ± 0.26). The pharmacokinetics of 123I-SB207710 and 123I-p-MPPI do not make them ideal tracers for preclinical SPECT neuroimaging. 123I-ADAM showed adequate brain uptake regardless of Mdr1a expression and appeared suitable for preclinical SPECT neuroimaging in both animal strains. The use of Mdr1a KO animals significantly improved the brain penetration of 123I-R91150, making this animal strain an interesting option when considering SPECT neuroimaging of 5-HT2A receptors in rat.

Change over time in brain serotonin transporter binding in major depression: effects of therapy measured with [(123) I]-ADAM SPECT.

Several studies have reported low brain serotonin transporter (SERT) binding in individuals with major depression. We hypothesized that the SERT standardized uptake ratio (SUR) values using [(123) I]-ADAM single photon emission computed tomography would increase in depressed subjects who responded to cognitive behavior therapy (CBT) compared to CBT nonresponders. [(123) I]-ADAM scans were acquired before and after 12 weeks of CBT from 20 depressed subjects and on two occasions 12 weeks apart from 10 nondepressed, healthy volunteers. The primary outcome measure was change over time in SUR values in the midbrain, medial temporal lobe, and basal ganglia regions. Depressed subjects demonstrated low pretreatment mean SUR values that significantly increased over time in the midbrain (P = .011), right medial temporal lobe (P = .008), and left medial temporal lobe (P = .000) regions. Treatment responders showed a significant increase over time in SUR values in left medial temporal lobe (P = .029) and right medial temporal lobe (P = .007) regions. Partial and nonresponder subjects also showed a significant increase over time in SUR values in the left medial temporal region (P = .040) (vs. healthy volunteers), but to a lesser degree. The findings suggest that low pretreatment SERT binding may increase over time in some depressed individuals who experience symptom improvement.

No seasonal variation in human midbrain serotonin transporter availability in Taiwan.

Sunlight exposure is considered responsible for seasonal serotonin changes. Sixty-six healthy participants were recruited, and single photon emission computed tomography ([¹²³I]-ADAM SPECT) was used to investigate the association between serotonin transporter (SERT) availability and duration of sunlight exposure in Taiwan, a subtropical country. No significant correlation between SERT availability and the duration of sunlight exposure was found.

Short term vs. long term test-retest reproducibility of ¹²³I-ADAM for the binding of serotonin transporters in the human brain.

Previous brain imaging studies have demonstrated a seasonal difference of serotonin transporter (SERT) binding in the human brain. However, the results were somewhat contradictory. We conducted test-retest study with single photon emission computed tomography (SPECT) with ¹²³I-ADAM as ligand in 28 healthy subjects. Ten of the subjects were studied within 1 month, whereas 18 were randomly assigned to be studied over a period of up to 1 year. The primary measure was the specific uptake ratio (SUR). Regions of interest included the midbrain, thalamus, putamen and caudate. The intra-class correlation coefficient (ICC) was 0.52-0.94 across different brain regions over 1 month, whereas the ICC was -0.24-0.63 over a 1-year period. The 1-month variability ranged from 6.5 ± 5.1% to 12.5 ± 10.6% across different brain regions, and the 1-year variability ranged from 16.5 ± 9.6% to 41.9 ± 35.5%. The Kruskal-Wallis test revealed a significant difference of variability across months. The Wilcoxon Signed Ranks Test showed the SUR between test-retest scans was of borderline significance. Curve fitting, using a 4th degree polynomial model, revealed a significant circadian correlation between the variability and interval of test-retest measurements. Our findings demonstrate the test-retest reproducibility of ¹²³I-ADAM in different time periods and suggest that circadian variation of SERT levels in the human brain might exist.

Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study.

OBJECTIVES: Previous positron emission tomography studies have demonstrated that serotonin transporter (SERT) binding in the midbrain is decreased in the depressive state of bipolar disorder (BD). The aim of this study was to assess SERT binding in the midbrain of patients in a euthymic state of BD. METHODS: Twenty-eight healthy controls and 24 patients in a euthymic state of medicated BD were recruited. Euthymic state was defined as Montgomery-Asberg Depression Rating Scale scores < 10 and Young Mania Rating Scale scores < 7 within a consecutive eight-week period. Single photon emission computed tomography with the radiotracer (123)I-ADAM was used to measure SERT binding in the midbrain. An equilibrium ratio model was used for data analysis. Specific uptake ratio (SUR), which represents availability of SERT binding in the midbrain, was the primary measurement outcome. RESULTS: The averaged SURs were not different between healthy controls and BD patients in euthymic state (p = 0.27). However, a three-way ANCOVA analysis comparing SURs in healthy controls, bipolar I disorder (BD I) patients, and bipolar II disorder (BD II) patients, covarying education duration and sex, showed that the averaged SURs were significantly lower in BD I than BD II patients and healthy controls (p = 0.042). The decreased SURs in BD I patients were well correlated with duration of illness (R = -0.742, p = 0.014) only. CONCLUSIONS: Our findings demonstrate that there is differential biological regulation in BD I and BD II patients after stable treatment, which may support the existence of a dichotomy in BD.

Imaging serotonin transporters using [123I]ADAM SPECT in a parkinsonian primate model.

Parkinson's disease (PD) affects multiple neurotransmitter systems. The purpose of this study was to investigate differences in the serotonin transport system between normal and parkinsonian monkeys using 2-([2-([di-methylamino]methyl)phenyl]thio)-5-[(123)I] iodophenyl-amine([(123)I]ADAM), a serotonin transporters (SERT) radioligand. The brain single photon emission computed tomography (SPECT) was performed on two normal and one parkinsonian monkey. The parkinsonian monkey was induced by bilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle under magnetic resonance imaging (MRI) guidance. Each monkey underwent two [(99m)Tc] TRODAT-1 (a dopamine transporters imaging agent) and two [(123)I] ADAM brain SPECT scans. After a bolus injection of the radioligand, the SPECT data were acquired over 4h using a dual-head gamma camera equipped with ultra-high resolution fan-beam collimators. The striatal uptake of [(99m)Tc]TRODAT-1 was 46% lower in the parkinsonian monkey than those of normal monkeys at 210-240 min post-injection. [(123)I]ADAM uptake in the midbrain of the parkinsonian monkey was comparable to those of the controls. The uptakes of [(123)I]ADAM in the striatum, thalamus, and frontal cortex of the parkinsonian monkey, were 31%, 31%, and 23% lower than those of normal monkeys at 210-240 min post-injection, respectively. Our results suggest that [(123)I]ADAM SPECT has potential for evaluating the serotonin transporter changes in human PD.

Evaluation of reference tissue model and tissue ratio method for 5-HTT using [(123)I] ADAM tracer.

The serotonin (5-hydroxytryptamine, or 5-HT) transporters (5-HTT) are target-sites for commonly used antidepressants. [(123)I] ADAM is a novel radiotracer that selectively binds the 5-HTT of the central nervous system. The aim for this study was to compare four-parameter model (FPM) with three-parameter model (TPM) from non-invasive reference tissue model (RTM) for 5-HTT quantification using the cerebellum as indirect input function. Furthermore, we compared tracer kinetic model with the tissue ratio (TR) method. The binding potential (BP) values derived from both models were almost the same, but ratio of delivery (R(1)) in TPM had smaller standard deviation than the FPM. There was also significant correlation between BP and specific uptake ratio (SUR). In conclusion, simplified reference tissue model (SRTM) was the better choice because of its stability and convenient implementation for non-invasive quantification of brain SPECT studies. The correlation found between BP and SUR supports the use of TR method for quantification of 5-HTT to avoid arterial sampling in dynamic SPECT scan.

123I-ADAM SPECT imaging of serotonin transporter binding in patients with night eating syndrome: a preliminary report.

Night eating syndrome (NES) represents a delay in the circadian pattern of food intake, manifested by evening hyperphagia and/or nocturnal awakenings accompanied by ingestions of food. A neurobiological marker of NES has been implicated with the recently discovered therapeutic response to the selective serotonin reuptake inhibitor (SSRI) sertraline. This pilot SPECT (single photon emission computed tomography) study compared the serotonin transporter (SERT) uptake ratios of night eaters with those of healthy controls. Six night eaters underwent SPECT imaging using the radiopharmaceutical (123)I-ADAM. Uptake, compared with that of the cerebellum, was obtained for the midbrain, basal ganglia, and temporal lobes; uptake ratios in night eaters were compared with those of six healthy controls. Night eaters had significantly greater SERT uptake ratios in the midbrain than healthy controls. These findings, in conjunction with the therapeutic response of NES to sertraline, indicate that the serotonin system is involved in the pathophysiology of NES.

Evaluation of the Serotonin Transporter Ligand 123I-ADAM for SPECT Studies on Humans.

UNLABELLED: Imaging serotonin transporters in the living human brain is important in several fields, such as normal psychophysiology, mood disorders, eating disorders, and neurodegenerative disorders. The aim of this study was to compare different kinetic and semiquantitative methods for assessing serotonin transporters using (123)I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) in humans: an arterial plasma input model, simplified and Logan reference tissue models, and standardized uptake value ratios. METHODS: Nine subjects were scanned with dynamic (123)I-ADAM SPECT (mean age, 31 y; range, 24-43 y), and metabolite-corrected arterial input was measured. Tissue reference models (simplified reference tissue model, Logan reference tissue model, and ratio method) were validated against the outcome of a 1-tissue-compartment model, and performance with decreasing scan length was evaluated. The specificity of (123)I-ADAM binding was investigated in a blocking experiment. RESULTS: Binding estimates from the simplified reference tissue and Logan reference tissue models correlated tightly with full kinetic modeling when based on a 240- or 360-min dynamic acquisition (r = 0.99); however, there were slight underestimations (3%-5%), especially in high-binding regions. Application of the ratio method to data from 200 to 240 min overestimated specific binding (on average, by 10% +/- 28%) and correlated only moderately with estimates from the 1-tissue-compartment model (r = 0.94). With an acquisition time of 0-120 min, the Logan model still yielded an acceptable outcome when a fixed clearance rate constant (k2') from the cerebellum was applied. Intravenously injected citalopram was not associated with a decrease in cerebellar binding. A lipophilic metabolite that did not seem to bind specifically to serotonin transporter was seen in 2 of 7 subjects. CONCLUSION: Serotonin transporter binding with (123)I-ADAM SPECT can be assessed with the Logan model based on a 120-min acquisition when a constant k2' is applied. This model, because it allows for more accurate and less biased binding estimates and thus reduces the required sample size, is advantageous over the ratio method used in clinical studies so far. A single blocking experiment supported the use of the cerebellum as a reference region.

Association between serotonin transporter availability and hostility scores in healthy volunteers - a single photon emission computed tomography study with [(123)I] ADAM.

The present study examined the relationship between serotonin transporter (SERT) availability and hostility scores in healthy volunteers. SERT availability was measured by using SPECT with [(123)I] ADAM in 10 healthy participants. Hostility was measured with the Cook-Medley Hostility Scale. Hostile attribution, but not the other subscales of hostility, was negatively correlated with SERT availability. Central serotoninergic activities may play a role in hostility.

Binding kinetics of 123I[ADAM] in healthy controls: a selective SERT radioligand.

[123I]ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) is a promising radioligand for in-vivo quantification of serotonin transporters (SERT) using single photon emission computed tomography (SPECT) in man. We performed tracer kinetic analysis in various brain regions to determine the optimum equilibrium time for SERT quantification with [123I]ADAM and SPECT. Radiosyntheses of [123I]ADAM were performed at MAP Medical Technologies Oy, Tikkakoski, Finland. Thirty healthy male volunteers (21-41 yr) received between 104 and 163 MBq [123I]ADAM intravenously as a bolus. Consecutively, multiple SPECT scans were performed between 14 and 420 min post-injection (p.i.) using a Siemens Multispect 3 camera. Reconstruction was performed applying filtered back projection with a Butterworth filter (cut-off 0.7, order 7) in 128x128 matrices. Regions of interest (ROI) were drawn manually on the individual T1-weighted magnetic resonance image (MRI) comprising midbrain/hypothalamus for specific binding to SERT, and the cerebellum as reference region. After re-orientation to the MRI, the ROI template was applied to SPECT studies. We generated time-activity curves for the ROI and calculated the ratio countstarget/countscerebellum minus 1 (=V3'') as a measure for specific SERT binding. Counts were corrected for applied activity, acquisition time and body-weight. Peak uptakes were observed between 14 and 50 min after bolus injection. Counts per voxel were highest in the midbrain/hypothalamus, 798 (max. 872, min. 728), whereas 462 counts per voxel (max. 599, min. 412) were measured in the cerebellum at a mean time of 31 min p.i. Stable values for V3'' reached 205-320 min p.i. Mean peak V3'' value was 1.43 (95% CI 171-230) for the midbrain/hypothalamus at 205 min p.i. [123I]ADAM is a useful ligand for in-vivo quantification of human SERT by means of SPECT, with a comparatively better signal-to-noise ratio compared to beta-CIT. Our data suggest that the acquisition time for the SPECT scan is optimally, under pseudo-equilibrium conditions, between 205-320 min post-bolus injection of the tracer.

Brain kinetics of the new selective serotonin transporter tracer [(123)I]ADAM in healthy young adults.

UNLABELLED: Recently, the tracer (123)I-2-([2-({dimethylamino}methyl)phenyl]thio)-5-iodophenylamine ([(123)I]ADAM) has been developed for selective imaging of serotonin transporters (SERTs) with single photon emission computed tomography (SPECT). The purpose of this study was to develop an [(123)I]ADAM SPECT protocol for clinical studies in young adults. METHODS: We examined the time course of [(123)I]ADAM binding to central SERTs in eight healthy young volunteers up to 6 h postinjection. RESULTS: We found that the time of peak-specific [(123)I]ADAM binding was highly variable among subjects, but specific binding in the SERT-rich (hypo)thalamus peaked within 5 h postinjection in all subjects. Moreover, in this brain area, binding ratios of specific to nonspecific binding did not significantly change between 3 and 6 h postinjection, and peaked 5 h postinjection. CONCLUSIONS: Five hours postinjection may be optimal for single-scan [(123)I]ADAM SPECT studies in humans, but more work is needed to assess the accuracy of the 5-h tissue ratio as a measure of SERT in the brain.

Brain SPECT imaging and whole-body biodistribution with [(123)I]ADAM - a serotonin transporter radiotracer in healthy human subjects.

INTRODUCTION: [(123)I]-2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([(123)I]ADAM), a novel radiotracer, has promising application in the imaging of the serotonin transporter (SERT) in the human brain. In this study, the optimal scanning time for acquiring brain single photon emission computed tomography (SPECT) images was determined by performing dynamic SPECT studies at intervals from 0 to 6 h postinjection of [(123)I]ADAM. Additionally, radiation-absorbed doses were determined for three healthy human subjects using attenuation-corrected images. METHODS: Twelve subjects were randomized into one of three study groups as follows: whole-body distribution imaging (n=3), dynamic SPECT imaging (n=3) and brain SPECT imaging (n=6). The radiation-absorbed dose was calculated using MIRDOSE 3.0 software with attenuation-corrected data. The specific binding (SB) ratio of the brain stem was measured from dynamic SPECT images to determine the optimal scanning time. RESULTS: Dynamic SPECT images showed that the SB of the brain stem gradually increased to a maximum 4 h postinjection. Single photon emission computed tomography images at 4 h postinjection showed a high uptake of the radiotracer (SB) in the hypothalamus (1.40+/-0.12), brain stem (1.44+/-0.16), pons (1.13+/-0.14) and medial temporal lobe (0.59+/-0.10). The mean adult male value of effective dose was 3.37 x 10(-2) mSv/MBq with a 4.8-h urine-voiding interval. Initial high uptake in SERT-rich sites was demonstrated in the lung and brain. A prominent washout of the radiotracer from the lung further increased brain radioactivity that reached a peak value of 5.03% of injected dose 40 min postinjection. CONCLUSIONS: [(123)I]ADAM is a promising radiotracer for SPECT imaging of SERT in humans with acceptable dosimetry and high uptake in SERT-rich regions. Brain SPECT images taken within 4 h following injection show optimal levels of radiotracer uptake in known SERT sites. However, dynamic changes in lung SERT distribution must be carefully evaluated.

Imaging of serotonin transporters and its blockade by citalopram in patients with major depression using a novel SPECT ligand [123I]-ADAM.

We studied the midbrain SERT availability in patients with major depression and assessed the relation of SERT occupancy by citalopram to the treatment response. 21 non-medicated patients with major depression and 13 healthy controls were examined by [(123)I]-ADAM SPECT. The midbrain SERT availability (SERT V(3)'') was calculated using individual MRI scans. In 13/21 patients SPECT was repeated 7 days after oral medication with citalopram (10 mg/day). We found no significant difference in the mean midbrain SERT availability between the studied patients with major depression and healthy controls (0.86 +/- 0.27 vs. 0.71 +/- 0.44, p = 0.069). The mean SERT occupancy accounted to 61%. The degree of SERT blockade by citalopram did not correlate with the reduction in HAMD total score. Treatment with low-dosed citalopram caused individually variable occupancy of the midbrain-SERT and a rapid clinical improvement in 54% of the investigated patients.

Measuring SSRI occupancy of SERT using the novel tracer [123I]ADAM: a SPECT validation study.

PURPOSE: Serotonergic brain regions play a crucial role in the modulation of emotion, and serotonergic dysfunction may contribute to several neurological disorders. [123I]ADAM is a novel SPECT tracer which binds with high affinity to serotonin transporters (SERT). The objective of this study was to compare different methods for the quantification of tracer binding and to develop a simplified single-scan protocol for this tracer, as well as to investigate its potential for characterisation of the transporter occupancy versus plasma concentration curve of a selective serotonin re-uptake inhibitor (SSRI). METHODS: Dynamic SPECT scans were performed on 16 healthy volunteers after administration of approximately 150 MBq [123I]ADAM. Data were acquired from the time of injection until approximately 5.5 h after injection in 30- or 45-min sessions. Each subject was scanned twice: with and without pre-treatment with the SSRI citalopram in various dosage regimens. The plasma concentration of citalopram (C(p)) was determined from venous samples. Images were reconstructed by filtered back-projection with scatter and attenuation correction. Tracer binding was quantified for midbrain, striatum and thalamus using cerebellum as a reference region. Quantification was done by kinetic modelling, graphical analysis and multi-linear regression, as well as by the ratio method, with binding potential (BP2) as the outcome measure. The SERT occupancy by citalopram was determined relative to the baseline scan for each subject, and the occupancy versus C(p) curve was fitted with the E(max) model. RESULTS: The highest binding of [123I]ADAM was in midbrain (mean baseline BP2+/-SD=1.31+/-0.29), with lower binding in thalamus (0.79+/-0.16) and striatum (0.66+/-0.13). There was good agreement between BP2 values obtained by different quantification methods. Using the ratio method, the best agreement with kinetic modelling was obtained with data from the time interval [200,260] min after injection. The fitting of the midbrain occupancy curve yielded a maximum occupancy of 84% and a plasma concentration required to reach 50% of the maximum of 2.5 ng/ml, with a goodness-of-fit variability of 13% (SD). CONCLUSION: Binding of [123I]ADAM to SERT in midbrain can be quantified with a single scan starting 200 min after injection. However, the variability of estimated occupancy values may be too high for critical assessment of occupancy of SERT by SSRI.

SPECT of serotonin transporters using 123I-ADAM: optimal imaging time after bolus injection and long-term test-retest in healthy volunteers.

UNLABELLED: (123)I-ADAM (2-([2-([dimethylamino]methyl)phenyl]thio)-5-(123)I-iodophenylamine) has been recently proposed as a new serotonin transporter (SERT) ligand for SPECT. The objective of this study was to characterize (123)I-ADAM in healthy volunteers. (123)I-ADAM distribution in the normal brain, pseudoequilibrium interval after a single injection, normal specific uptake values, and long-term test-retest variability and reliability were investigated. METHODS: Ten healthy volunteers underwent 2 SPECT sessions under the same conditions 47.6 +/- 24.0 d apart. Scans were sequentially acquired from the time of (123)I-ADAM intravenous injection up to 12 h after injection. Regions of interest (ROIs) for cerebellum (C), midbrain, thalamus, striatum, mesial temporal region, and cortex were drawn on MR images and pasted to corresponding SPECT slices after coregistration. Specific uptake ratios (SURs) at pseudoequilibrium and the simplified reference tissue model (SRTM) methods were used for quantification. SURs were obtained as ([region - C]/C) at each time point. Test-retest variability and reliability (intraclass correlation coefficient [ICC]) were calculated. RESULTS: The highest (123)I-ADAM specific uptake was found in the midbrain and thalamus, followed by the striatum and mesial temporal region. Quantification results using SUR and SRTM were correlated with R = 0.93 (test) and R = 0.94 (retest). SURs remained stable in all regions from 4 to 6 h after injection. Using SUR, test-retest variability/ICC were 13% +/- 11%/0.74 in midbrain, 16% +/- 13%/0.63 in thalamus, 19% +/- 18%/0.62 in striatum, and 22% +/- 19%/0.05 in mesial temporal region. CONCLUSION: (123)I-ADAM accumulates in cerebral regions with high known SERT density. The optimal imaging time for (123)I-ADAM SPECT quantification is suggested to be from 4 to 6 h after a single injection. Long-term test-retest variability and reliability found in the midbrain are comparable to that reported with other (123)I-labeled SPECT ligands. These results support the use of (123)I-ADAM SPECT for SERT imaging after a single injection in humans.

In vivo quantification by SPECT of [123I] ADAM bound to serotonin transporters in the brains of rabbits.

BACKGROUND: A novel radioiodine ligand [(123)I] ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine) has been suggested as a promising serotonin transporter (SERT) imaging agent for the central nervous system. In this study, the biodistribution of SERTs in the rabbit brain was investigated using [(123)I] ADAM and mapping images of the same animal produced by both single-photon emission computed tomography (SPECT) and microautoradiography. A semiquantification method was adopted to deduce the optimum time for SPECT imaging, whereas the input for a simple fully quantitative tracer kinetic model was provided from arterial blood sampling data. METHODS: SPECT imaging was performed on female rabbits postinjection of 185 MBq [(123)I] ADAM. The time-activity curve obtained from the SPECT images was used to quantify the SERTs, for which the binding potential was calculated from the kinetic modeling of [(123)I] ADAM. The kinetic data were analyzed by the nonlinear least squares method. The effects of the selective serotonin reuptake inhibitors fluoxetine and p-chloroamphetamine (PCA) on rabbits were also evaluated. After scanning, the same animal was sacrificed and the brain was removed for microautoradiography. Regions-of-interest were analyzed using both SPECT and microautoradiography images. The SPECT images were coregistered manually with the corresponding microautoradiography images for comparative study. RESULTS: During the time interval 90-100 min postinjection, the peak specific binding levels in different brain regions were compared and the brain stem was shown to have the highest activity. The target-to-background ratio was 1.89+/-0.02. Similar studies with fluoxetine and PCA showed a background level for SERT occupation. Microautoradiography demonstrated a higher level of anatomical details of the [(123)I] ADAM distribution than that obtained by SPECT imaging of the rabbit brain. CONCLUSION: SPECT imaging of the rabbit brain with [(123)I] ADAM showed high affinity, high specificity, and favorable kinetics. The time-activity curve showed that the accumulation of the [(123)I] ADAM in the brain stem reached a maximum between 90 and 100 min postinjection. The microautoradiography provides high-resolution images of the rabbit brain. Our results for the [(123)I] ADAM biodistribution in the rabbit brains demonstrate that this new radioligand is suitable as a selective SPECT imaging agent for SERTs.

Microautoradiography of [123I]ADAM in mice treated with fluoxetine and serotonin reuptake inhibitors.

A radiopharmaceutical, (123)I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine ([(123)I]ADAM), has been developed recently for evaluation of how serotonin transporters (SERT) function in the brain. However, the detailed biodistribution and specific binding in certain brain areas are not well investigated. In this study, both phosphor plate imaging and microautoradiography were applied to explore the binding characteristics of [(123)I]ADAM in SERT neurons. The effect of two psychotropics and one narcotic on the binding of [(123)I]ADAM to SERT was also studied. Fluoxetine and desipramine, both are psychotropics and specific SERT ligands and decreased the affinity of [(123)I]ADAM, while p-chloroamphetamine (PCA), a narcotic, destroyed most of serotonergic neurons, as well as reducing the concentration of serotonin and the number of SERT in the brain as shown by the biodistribution of [(123)I]ADAM. Significant and selective accumulation of [(123)I]ADAM in the areas from midbrain to brain stem in normal mice with maximum target-to-background ratio was found at 90 minutes postinjection. A rapid clearance of [(131)I]ADAM at 120 minutes postinjection was found in the CA1, CA3 and ThN brain areas. In addition, the inhibition effect on binding ability of [(123)I]ADAM to SERT by the psychotropics and the narcotic was found to have the order of: PCA > fluoxetine > desipramine.