Biodistribution and radiation dosimetry of the norepinephrine transporter radioligand (S,S)-[18F]FMeNER-D2: a human whole-body PET study

Takano, Akihiro; Halldin, Christer; Varrone, Andrea; Karlsson, Per; Sjöholm, Nils; Stubbs, James B.; Schou, Magnus; Airaksinen, Anu J.; Tauscher, Johannes; Gulyás, Balázs

doi:10.1007/s00259-007-0622-z

Cited by 18 publications

(7 citation statements)

References 23 publications

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“…The rapid elimination of radioactivity from blood following 123 I‐NKJ64 injection supports the efficient delivery of the radiotracer to the tissues. Radioactivity rapidly entered the lungs, reaching a maximum of 6% of injected dose consistent with previous reports of significant lung uptake for other NAT radiotracers (Kanegawa et al,2006; Kiyono et al,2004; Kung et al,2004; Lakshmi et al,2008; McConathy et al,2004; Takano et al,2008a). Both Kiyono et al (2004) and Kanegawa et al (2006) reported significant uptake in the lungs of 125 I‐MIPP and 125 I‐IPBM, respectively.…”

Section: Discussionsupporting

confidence: 88%

¹²³I‐NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

Tavares

Jobson

Dewar

et al. 2011

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Dysregulation of noradrenergic function has been implicated in a variety of psychiatric and neurodegenerative disorders, including depression and Alzheimer's disease. The noradrenaline transporter (NAT) is a major target for antidepressant drugs, including reboxetine, a selective noradrenaline reuptake inhibitor. Therefore, the development of a radiotracer for imaging of the NAT is desirable. In this study, NKJ64, a novel iodinated analog of reboxetine, was radiolabeled and evaluated as a potential single photon emission computerized tomography (SPECT) radiotracer for imaging the NAT in brain. Biological evaluation of the novel radiotracer, ¹²³/¹²⁵I-NKJ64, was carried out in rats using: in vitro ligand binding assays; in vitro and ex vivo autoradiography; in vivo biodistribution studies and ex vivo pharmacological blocking studies. ¹²⁵I-NKJ64 displayed saturable binding with high affinity for NAT in cortical homogenates (K(D) = 4.82 ± 0.87 nM, mean ± SEM, n = 3). In vitro and ex vivo autoradiography showed the regional distribution of ¹²³I-NKJ64 binding to be consistent with the known density of NAT in brain. Following i.v. injection there was rapid uptake of ¹²³I-NKJ64 in brain, with maximum uptake of 2.93% ± 0.14% (mean ± SEM, n = 3) of the injected dose. The specific to nonspecific ratio (locus coeruleus:caudate putamen) of ¹²³I-NKJ64 uptake measured by ex vivo autoradiography was 2.8 at 30 min post i.v. injection. The prior administration of reboxetine significantly reduced the accumulation of ¹²³I-NKJ64 in the locus coeruleus (>50% blocking). The data indicate that further evaluation of ¹²³I-NKJ64 in nonhuman primates is warranted in order to determine its utility as a SPECT radiotracer for imaging of NAT in brain.

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Section: Discussionsupporting

confidence: 88%

¹²³I‐NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

Tavares

Jobson

Dewar

et al. 2011

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“…[ 18 F] 8 is labeled in a fluoromethoxy position which may be susceptible to radiodefluorination in human subjects in vivo to give high radioactivity uptake in bone including skull. Skull uptake of radioactivity is known to occur for other PET radioligands labeled with fluorine-18 in a fluoromethoxy position, including ( S , S )-[ 18 F]FMeNER-D 2 35 and [ 18 F]FMEPEP- d 2 36 . In fact the incorporation of deuterium into these radioligands is intended to counter radiodefluorination in vivo .…”

Section: Resultsmentioning

confidence: 99%

Radiosynthesis and Evaluation of an ¹⁸F-Labeled Positron Emission Tomography (PET) Radioligand for Brain Histamine Subtype-3 Receptors Based on a Nonimidazole 2-Aminoethylbenzofuran Chemotype

Bao

Liow

et al. 2012

J. Med. Chem.

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A known chemotype of H3 receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H3) receptors in vivo with positron emission tomography (PET), namely non-imidazole 2-aminoethylbenzofurans, represented by the compound (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)methanone (9). Compound 9 was labeled with fluorine-18 (t1/2= 109.7 min) in high specific activity by treating the prepared nitro analog (12) with cyclotron-produced [18F]fluoride ion. [18F]9 was studied with PET in mouse and in monkey after intravenous injection. [18F]9 showed favorable properties as a candidate PET radioligand, including moderately high brain uptake with a high proportion of H3 receptor-specific signal in the absence of radiodefluorination. The nitro compound 12 was found to have even higher H3 receptor affinity, indicating the potential of this chemotype for the development of further promising PET radioligands.

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“…The difference might be due to different doses and route administration of the blocking drug (nisoxetine): 2mg/kg (intravenous) vs. 10mg/kg (intraperitoneal) and/or due to the different fundamental pharmaceutical properties of these two tracers. On the other hand, a high lung uptake in human of another MRB derivative, (S,S)-[ 18 F]FMeNER-D2, was reported [20]. Its high lung accumulation was considered to be non-specific due to high-affinity amine binding sites in the macrophages in the lungs.…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo and In Vivo Evaluation of the Norepinephrine Transporter Ligand [11C]MRB for Brown Adipose Tissue Imaging

Lin

Fan

Yeckel

et al. 2012

Nuclear Medicine and Biology

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Introduction It has been suggested that brown adipose tissue (BAT) in humans may play a role in energy balance and obesity. We conducted ex vivo and in vivo evaluation using [11C]MRB, a highly selective NET (norepinephrine transporter) ligand for BAT imaging at room temperature which is not achievable with [18F]FDG. Methods PET images of male Sprague-Dawley rats with [18F]FDG and [11C]MRB were compared. Relative [18F]FDG or [11C]MRB retention at 20, 40 and 60 min post-injection was quantified on awake rats after exposing to cold (4°C for 4h) or remaining at room temperature. Rats pretreated with unlabeled MRB or nisoxetine 30 min before [11C]MRB injection were also assessed. The [11C]MRB metabolite profile in BAT was evaluated. Results PET imaging demonstrated intense [11C]MRB uptake (SUV of 2.9 to 3.3) in the interscapular BAT of both room temperature and cold-exposed rats and this uptake was significantly diminished by pretreatment with unlabeled MRB; in contrast, [18F]FDG in BAT was only detected in rats treated with cold. Ex vivo results were concordant with the imaging findings; i.e. the uptake of [11C]MRB in BAT was 3 times higher than that of [18F]FDG at room temperature (P=0.009), and the significant cold-stimulated uptake in BAT with [18F]FDG (10-fold, P=0.001) was not observed with [11C]MRB (P=0.082). HPLC analysis revealed 94-99% of total radioactivity in BAT represented unchanged [11C]MRB. Conclusions Our study demonstrates that BAT could be specifically labeled with [11C]MRB at room temperature and under cold conditions, supporting a NET-PET strategy for imaging BAT in humans under basal conditions.

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Biodistribution and radiation dosimetry of the norepinephrine transporter radioligand (S,S)-[18F]FMeNER-D2: a human whole-body PET study

Abstract: Based on the distribution and dose estimates, the estimated radiation burden of (S,S)-[(18)F]FMeNER-D(2) is lower than that of [(18)F]FDG. The radioligand would allow multiple PET examinations in the same research subject per year.

Cited by 18 publications

References 23 publications

¹²³I‐NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

¹²³I‐NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

Radiosynthesis and Evaluation of an ¹⁸F-Labeled Positron Emission Tomography (PET) Radioligand for Brain Histamine Subtype-3 Receptors Based on a Nonimidazole 2-Aminoethylbenzofuran Chemotype

Ex Vivo and In Vivo Evaluation of the Norepinephrine Transporter Ligand [11C]MRB for Brown Adipose Tissue Imaging

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Biodistribution and radiation dosimetry of the norepinephrine transporter radioligand (S,S)-[18F]FMeNER-D2: a human whole-body PET study

Abstract: Based on the distribution and dose estimates, the estimated radiation burden of (S,S)-[(18)F]FMeNER-D(2) is lower than that of [(18)F]FDG. The radioligand would allow multiple PET examinations in the same research subject per year.

Cited by 18 publications

References 23 publications

123I‐NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

123I‐NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

Radiosynthesis and Evaluation of an 18F-Labeled Positron Emission Tomography (PET) Radioligand for Brain Histamine Subtype-3 Receptors Based on a Nonimidazole 2-Aminoethylbenzofuran Chemotype

Ex Vivo and In Vivo Evaluation of the Norepinephrine Transporter Ligand [11C]MRB for Brown Adipose Tissue Imaging

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¹²³I‐NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

¹²³I‐NKJ64: A novel single photon emission computed tomography radiotracer for imaging the noradrenaline transporter in brain

Radiosynthesis and Evaluation of an ¹⁸F-Labeled Positron Emission Tomography (PET) Radioligand for Brain Histamine Subtype-3 Receptors Based on a Nonimidazole 2-Aminoethylbenzofuran Chemotype