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

Sacher, Julia; Asenbaum, S.; Klein, Nikolas; Geiss-Granadia, Thomas; Mossaheb, Nilufar; Poetzi, Christian; Attarbaschi, T.; Lanzenberger, Rupert; Spindelegger, Christoph; Rabas, Alexander; Heinze, Georg; Dudczak, Robert; Kasper, S.; Tauscher, Johannes

doi:10.1017/s1461145706006511

Cited by 7 publications

(4 citation statements)

References 31 publications

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“…This finding confirms a previous study on baboons that also found the simplified reference tissue model to underestimate specific binding, with an increasing bias for high-density regions (30). The clinical studies published so far have recommended use of a ratio between specific binding regions and cerebellum that includes time-activity curves from 200 to 360 min after injection, with a total acquisition time of 30-60 min (7,9,10,17). This recommendation is based on comparisons with simplified reference tissue model estimates from data generated by sequential acquisitions at 5.5-7 h after injection.…”

Section: Discussionmentioning

confidence: 99%

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

Frøkjær¹,

Pinborg²,

Madsen³

et al. 2008

J Nucl Med

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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 5 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% 6 28%) and correlated only moderately with estimates from the 1-tissue-compartment model (r 5 0.94). With an acquisition time of 0-120 min, the Logan model still yielded an acceptable outcome when a fixed clearance rate constant (k29) 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 k29 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.

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Section: Discussionmentioning

confidence: 99%

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

Frøkjær¹,

Pinborg²,

Madsen³

et al. 2008

J Nucl Med

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“…This time frame is considered optimal for semiquantification of specific radiotracer binding. 25,26 A 128 × 128 matrix was used for all acquisitions. The rotational radius was minimized to less than 13 cm in all cases.…”

Section: Spect Imagingmentioning

confidence: 99%

[123I] ADAM and SPECT in patients with borderline personality disorder and healthy control subjects

Schaaff¹,

Koch²,

Pöpperl³

et al. 2007

Pharmacopsychiatry

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Objective: Serotonergic dysfunction is considered to be involved in the pathophysiology of borderline personality disorder (BPD). The aim of this study was to investigate serotonin transporter availability in patients with BPD as a marker of the central serotonergic system. Methods: Eight unmedicated patients with BPD and 9 healthy control subjects received single photon emission computed tomography (SPECT) 4 hours after injection of 185 MBq [I-123] . As a measure of brain serotonin transporter (SERT) availability, ratios of specific-to-nonspecific [I-123] ADAM binding for the brainstem and hypothalamus were calculated with an occipital reference. Levels of impulsiveness and depressive symptoms were assessed with the Barratt Impulsiveness Scale and the Beck Depression Inventory. Results: Mean specific-to-nonspecific ratios showed a 43% higher brainstem and a 12% higher hypothalamus ADAM binding in patients, compared with control subjects. We found significant correlations of ADAM binding with both age and impulsiveness but not depression. Associations of BIS scores with ADAM binding remained significant after controlling for age and depression (r = 0.69, p < 0.01). Conclusion: The study provides evidence of a serotonergic dysfunction in patients with BPD and suggests a serotonergic component in the pathophysiology of the disorder. SERT binding reflected the level of impulsiveness as a common feature in BPD.Objectif : On considère que le dysfonctionnement sérotoninergique joue un rôle dans la pathophysiologie du trouble de personnalité limite (TPL). Cette étude visait à étudier, chez les patients atteints d'un TPL, la disponibilité du transporteur de la sérotonine comme marqueur du système sérotoninergique central. Méthodes : Huit patients atteints d'un TPL qui ne prenaient pas de médicament et neuf sujets témoins en bonne santé ont été soumis à une tomographie d'émission monophotonique (TEM) 4 heures après avoir reçu par injection 185 MBq [I-123] ). Pour mesurer la disponibilité du transporteur de la séroto-nine dans le cerveau (SERT), on a calculé des ratios de fixation spécifique:non spécifique [I-123] d'ADAM dans le tronc cérébral et l'hypothalamus en utilisant un point de référence occipital. On a évalué les niveaux d'impulsivité et de symptômes dépressifs au moyen de l'échelle d'impulsivité de Barratt (EIB) et du questionnaire de dépression de Beck. Résultats : Les ratios de fixation spécifique:non spé-cifique moyens ont montré que la fixation de l'ADAM était plus élevée de 43 % dans le tronc cérébral et de 12 % dans l'hypothalamus chez les patients comparativement aux sujets témoins. Nous avons constaté des liens importants entre la fixation de l'ADAM et à la fois l'âge et l'impulsivité, mais non la dépression. Les liens entre les résultats de l'EIB et la fixation de l'ADAM sont demeurés importants compte tenu de l'âge et de la dépression (r = 0,69, p < 0,01). Conclusion : L'étude présente des preuves de dysfonctionnement séro-toninergique chez les patients atteints de TPL et indique la présence d'un élé...

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“…Encouraging results from human studies using the leading PET imaging agent, [ 11 C]DASB (3) (Table 1) have demonstrated the potential of studying drug occupancy in living human brains [9][10][11][12][13][14]. Progress has also been made in imaging SERT binding sites in the brain by single photon emission computed tomography (SPECT) [15][16][17]. SPECT imaging studies using [ 123 I]ADAM (2) were performed to investigate SERT occupancies after a single dose of escitalopram or citalopram.…”

Section: Introductionmentioning

confidence: 99%

“…SPECT imaging studies using [ 123 I]ADAM (2) were performed to investigate SERT occupancies after a single dose of escitalopram or citalopram. A test-retest study showed that the drug occupancy in the brain could be correlated with the level of antidepressant dose with good reproducibility [13,15,16,[18][19][20].…”

Section: Introductionmentioning

confidence: 99%

5-Chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new serotonin transporter ligand

Oya

Choi

Kung

et al. 2007

Nuclear Medicine and Biology

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Two novel ligands with a 4′-substitution on the phenyl ring B of biphenylthiol: 5-chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine, 7, and 2-(2′-((dimethylamino) methyl)-4′-methoxyphenylthio)-5-iodobenzenamine, 8, were prepared and tested as potential serotonin transporter (SERT) imaging agents. The new ligands displayed extremely high binding affinities to SERT (K i = 0.22 ± 0.09 and 0.11 ± 0.04 nM, respectively), with very low binding affinities to dopamine and norepinephrine transporters (K i > 1, 000 nM). The corresponding [ 125 I]7 and [ 125 I] 8 were successfully prepared from the tri-n-butyltin derivatives. They showed good brain uptakes and prolonged retention after iv injection in rats (brain uptake was 1.77 and 0.98 %dose/g for [ 125 I] 7 and 0.92 and 0.29 %dose/g for [ 125 I]8 at 2 and 120 minutes, respectively). Significantly, [ 125 I]7 showed excellent uptake and prolonged retention in the hypothalamus, where the SERT concentration is the highest. The hypothalamus/cerebellum ratios (target to background ratios) were 4.24, 7.10, 8.24 and 12.6 at 2, 4, 6 and 12 hours, respectively. The hypothalamus/cerebellum ratios for [ 125 I]8 were 3.97, 5.57 and 5.06 at 1, 2 and 4 hours, respectively. Adding the 4′-iodo-group to the phenyl ring B of 7 appeared to reduce the rate of clearance from the brain, and the kinetics favored uptake and retention in the hypothalamus. The localization of [ 125 I]7 in the hypothalamus region in the brain of rats could be blocked by pretreatment with (+)McN5652, escitalopram and ADAM (2), all selective serotonin transporter ligands (at 2 mg/Kg dose, iv, 5 min pretreatment). Ex vivo autoradiograms of rat brain sections (at 4 hr after iv injection of [ 125 I]7) showed intense labeling in regions of the brain known to have high SERT density. The excellent selective uptake and retention in the hypothalamus region suggests that [ 123 I]7 is a potential lead compound for developing new imaging agents targeting SERT binding sites with single photon emission computed tomography (SPECT).

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

Cited by 7 publications

References 31 publications

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

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

[123I] ADAM and SPECT in patients with borderline personality disorder and healthy control subjects

5-Chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new serotonin transporter ligand

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

Cited by 7 publications

References 31 publications

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

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

[123I] ADAM and SPECT in patients with borderline personality disorder and healthy control subjects

5-Chloro-2-(2′-((dimethylamino)methyl)-4′-iodophenylthio)benzenamine: a new serotonin transporter ligand

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

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