Carbon-11 HOMADAM: A novel PET radiotracer for imaging serotonin transporters

Jarkas, Nachwa; Votaw, John R.; Voll, Ronald J.; Williams, Lawrence R.; Camp, Vernon M.; Owens, Michael J.; Purselle, David; Bremner, J. Douglas; Kilts, Clinton D.; Nemeroff, Charles B.; Goodman, Mark M.

doi:10.1016/j.nucmedbio.2004.11.007

Cited by 30 publications

(54 citation statements)

References 31 publications

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“…As expected, the binding affinities of 7 and 8 to SERT were excellent (K i = 0.22 ± 0.07 and 0.11 ± 0.04 nM, respectively), while the affinities to DAT and NET were very low (K i > 1, 000 nM). The results are consistent with the binding profiles reported for other biphenylthiol derivatives [35][36][37]39,40,42] (Table 2 and 3) showed that they penetrated the intact blood-brain barrier with initial brain uptakes of 1.77 and 0.92 %dose/organ at 2 min post iv injection, respectively. The brain uptake values showed a low, but steady, decline for both compounds.…”

Section: Biological Studies and Discussionsupporting

confidence: 91%

“…Up to this point, the development of SPECT or PET imaging agents targeting SERT binding sites has relied on four different core structures, 5-iodo-nitroquipazine [21][22][23], tropanes [24][25][26], (+)-McN5652 [27][28][29][30][31] and biphenylthiols [32][33][34][35][36][37][38][39][40]. Biphenylthiol derivatives, [ 123 I] IDAM (1) [41] and [ 123 I]ADAM (2) [39,42], have been evaluated as potential agents for SPECT because there are several unique benefits associated with using this core structure (Table 1).…”

Section: Introductionmentioning

confidence: 99%

“…The biphenylthiol core structure is neutral and relatively small, properties essential for penetrating the intact blood-brain barrier and delivering imaging agents to SERT binding sites in the brain. These distinctive features have attracted many researchers to work on this series of compounds [32][33][34][35][36][37]43].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Biological Studies and Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

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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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“…[207,208] Numerous compounds have now been reported which exploit the diphenylsulfide motif in order to take advantage of its high binding affinity at the SERT and compounds 41 – 51 have been radiolabeled with 11 C.[209–218] Comparison of [ 11 C] 35 , [ 11 C] 41 , [ 11 C] 42 , [ 11 C] 44 , and [ 11 C] 49 indicated that [ 11 C] 42 had the fastest kinetics whereas [ 11 C] 49 had the highest signal-to-noise ratio. [213] Comparison between [ 11 C] 42 and [ 11 C] 45 in the same anesthetized rhesus monkey indicated that [ 11 C] 45 achieved higher uptake ratios than [ 11 C] 42 and also reached peak uptake faster.…”

Section: Serotonin Transporter (Sert)mentioning

confidence: 99%

Fluorine-18 Radiolabeled PET Tracers for Imaging Monoamine Transporters: Dopamine, Serotonin, and Norepinephrine

Stehouwer

Goodman

2009

PET Clinics

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SynopsisThis review focuses on the development of fluorine-18 radiolabeled PET tracers for imaging the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). All successful DAT PET tracers reported to date are members of the 3β-phenyl tropane class and are synthesized from cocaine. Currently available carbon-11 SERT PET tracers come from both the diphenylsulfide and 3β-phenyl nortropane class, but so far only the nortropanes have found success with fluorine-18 derivatives. NET imaging has so far employed carbon-11 and fluorine-18 derivatives of reboxetine but due to defluorination of the fluorine-18 derivatives further research is still necessary.

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“…11 C]HOMADAM ([ 11 C]N,N-dimethyl-2-(2 0 -amino-4 0 -hydroxymethylphenylthio)benzylamine) 13 were also developed and evaluated in humans.…”

Section: Introductionmentioning

confidence: 99%

Tracer Kinetic Modeling of [¹¹C]AFM, a New PET Imaging Agent for the Serotonin Transporter

Naganawa

Nabulsi

Planeta

et al. 2013

J Cereb Blood Flow Metab

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11 C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [11 C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time-activity curves were well described by MA1. The rank order of INTRODUCTIONThe serotonin transporter (SERT) is located on the presynaptic terminals of neurons, and is responsible for the reuptake of serotonin, a neurotransmitter involved in the regulation of brain functions such as mood, appetite, and sleep.1 Serotonin transporter is a primary target of action for selective serotonin reuptake inhibitors, which are effective therapeutic agents for the treatment of major depressive disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and other mood and anxiety disorders. Because the serotonin system has such an important role in the pathophysiology of these diseases, there has been considerable interest in developing in vivo positron emission tomography (PET) radioligands for imaging SERT distribution. In the human brain, highest concentrations of SERT are found in the raphe nucleus and midbrain, followed by thalamus, striatum, and amygdala. Intermediate levels are in the limbic system (hippocampus and cingulate cortex), and lower levels in the neocortex regions, with cerebellum displaying lowest to negligible SERT density.

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Carbon-11 HOMADAM: A novel PET radiotracer for imaging serotonin transporters

Cited by 30 publications

References 31 publications

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

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

Fluorine-18 Radiolabeled PET Tracers for Imaging Monoamine Transporters: Dopamine, Serotonin, and Norepinephrine

Tracer Kinetic Modeling of [¹¹C]AFM, a New PET Imaging Agent for the Serotonin Transporter

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Carbon-11 HOMADAM: A novel PET radiotracer for imaging serotonin transporters

Cited by 30 publications

References 31 publications

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

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

Fluorine-18 Radiolabeled PET Tracers for Imaging Monoamine Transporters: Dopamine, Serotonin, and Norepinephrine

Tracer Kinetic Modeling of [11C]AFM, a New PET Imaging Agent for the Serotonin Transporter

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Tracer Kinetic Modeling of [¹¹C]AFM, a New PET Imaging Agent for the Serotonin Transporter