Radiosynthesis and first preclinical evaluation of the novel norepinephrine transporter pet-ligand [11C]ME@HAPTHI

Rami‐Mark, Christina; Berroterán-Infante, Neydher; Philippe, Cécile; Foltin, Stefanie; Vraka, Chrysoula; Hoepping, Alexander; Lanzenberger, Rupert; Hacker, Marcus; Mitterhauser, Markus; Wadsak, Wolfgang

doi:10.1186/s13550-015-0113-3

Cited by 11 publications

(5 citation statements)

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“…The availability of PET markers for quantifying NET fiber density in the human brain means LC fiber density could be assessed in imaging studies [53–56]. An aging-related decline in LC NET [54] consistent with LC volume loss with age in humans [4] has been observed.…”

Section: Discussionmentioning

confidence: 99%

An experimental model of Braak’s pretangle proposal for the origin of Alzheimer’s disease: the role of locus coeruleus in early symptom development

et al. 2019

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Background The earliest brain pathology related to Alzheimer’s disease (AD) is hyperphosphorylated soluble tau in the noradrenergic locus coeruleus (LC) neurons. Braak characterizes five pretangle tau stages preceding AD tangles. Pretangles begin in young humans and persist in the LC while spreading from there to other neuromodulatory neurons and, later, to the cortex. While LC pretangles appear in all by age 40, they do not necessarily result in AD prior to death. However, with age and pretangle spread, more individuals progress to AD stages. LC neurons are lost late, at Braak stages III–IV, when memory deficits appear. It is not clear if LC hyperphosphorylated tau generates the pathology and cognitive changes associated with preclinical AD. We use a rat model expressing pseudohyperphosphorylated human tau in LC to investigate the hypothesis that LC pretangles generate preclinical Alzheimer pathology. Methods We infused an adeno-associated viral vector carrying a human tau gene pseudophosphorylated at 14 sites common in LC pretangles into 2–3- or 14–16-month TH-Cre rats. We used odor discrimination to probe LC dysfunction, and we evaluated LC cell and fiber loss. Results Abnormal human tau was expressed in LC and exhibited somatodendritic mislocalization. In rats infused at 2–3 months old, 4 months post-infusion abnormal LC tau had transferred to the serotonergic raphe neurons. After 7 months, difficult similar odor discrimination learning was impaired. Impairment was associated with reduced LC axonal density in the olfactory cortex and upregulated β1-adrenoceptors. LC infusions in 14–16-month-old rats resulted in more severe outcomes. By 5–6 months post-infusion, rats were impaired even in simple odor discrimination learning. LC neuron number was reduced. Human tau appeared in the microglia and cortical neurons. Conclusions Our animal model suggests, for the first time, that Braak’s hypothesis that human AD originates with pretangle stages is plausible. LC pretangle progression here generates both preclinical AD pathological changes and cognitive decline. The odor discrimination deficits are similar to human odor identification deficits seen with aging and preclinical AD. When initiated in aged rats, pretangle stages progress rapidly and cause LC cell loss. These age-related outcomes are associated with a severe learning impairment consistent with memory decline in Braak stages III–IV. Electronic supplementary material The online version of this article (10.1186/s13195-019-0511-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

An experimental model of Braak’s pretangle proposal for the origin of Alzheimer’s disease: the role of locus coeruleus in early symptom development

et al. 2019

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“…Furthermore, the tracer shows excellent metabolic stability in human liver microsomes with > 99% intact after 60 min incubation. Autoradiography on human brain tissue has revealed NET-specific uptake in NETrich regions (Rami-Mark et al 2015). Notably, in addition to CNS uptake, significant cardiac uptake of 11 C-Me@ HAPTHI has been observed, albeit with a more lipophilic chemical structure than abovementioned radiotracers.…”

Section: C-me@hapthimentioning

confidence: 99%

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

et al. 2020

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The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the therapeutic applications against certain types of neuroendocrine tumors, as exemplified by the clinically used 123/131 I-MIBG as theranostic single-photon emission computed tomography (SPECT) agent. With the development of more advanced positron emission tomography (PET) technology, more radiotracers targeting NET have been reported, with superior temporal and spatial resolutions, along with the possibility of functional and kinetic analysis. More recently, fluorine-18-labelled NET tracers have drawn increasing attentions from researchers, due to their longer radiological half-life relative to carbon-11 (110 min vs. 20 min), reduced dependence on on-site cyclotrons, and flexibility in the design of novel tracer structures. In the heart, certain NET tracers provide integral diagnostic information on sympathetic innervation and the nerve status. In the central nervous system, such radiotracers can reveal NET distribution and density in pathological conditions. Most radiotracers targeting cardiac NET-function for the cardiac application consistent of derivatives of either norepinephrine or MIBG with its benzylguanidine core structure, e.g. 11 C-HED and 18 F-LMI1195. In contrast, all NET tracers used in central nervous system applications are derived from clinically used antidepressants. Lastly, possible applications of NET as selective tracers over organic cation transporters (OCTs) in the kidneys and other organs controlled by sympathetic nervous system will also be discussed.

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“…Subsequently, [ 11 C]CO 2 was converted into [ 11 C]CH 4 by a Ni-catalyzed reduction with H 2 at 400 °C. The [ 11 C]CH 3 I was produced using gas phase conversion, as described in a previous study [18]. In short, the resulting [ 11 C]CH 4 was reacted with sublimated iodine at 738 °C in a recirculating process for 5 min to give [ 11 C]CH 3 I.…”

Section: Methodsmentioning

confidence: 99%

Optimization of the Automated Synthesis of [11C]mHED—Administered and Apparent Molar Activities

et al. 2019

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The tracer [[11C]meta-Hydroxyephedrine ([[11C]mHED) is one of the most applied PET tracers for cardiac imaging, whose radiosynthesis was already reported in 1990. While not stated in the literature, separation difficulties and an adequate formulation of the product are well known challenges in its production. Furthermore, the precursor (metaraminol) is also a substrate for the norepinephrine transporter, and can therefore affect the image quality. This study aims at optimizing the synthetic process of [[11C]mHED and investigating the effect of the apparent molar activity (sum of mHED and metaraminol) in patients and animals. The main optimization was the improved separation through reverse phase-HPLC by a step gradient and subsequent retention of the product on a weakly-cationic ion exchange cartridge. The µPET/µCT was conducted in ten rats (ischemic model) and the apparent molar activity was correlated to the VOI- and SUV-ratio of the myocardium/intra-ventricular blood pool. Moreover, nine long-term heart transplanted and five Morbus Fabry patients underwent PET and MRI imaging for detection of changes in the sympathetic innervation. In summary, the fully-automated synthesis and optimized purification method of [[11C]mHED is easily applicable and reproducible. Moreover, it was shown that the administered apparent molar activities had a negligible effect on the imaging quality.

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Radiosynthesis and first preclinical evaluation of the novel norepinephrine transporter pet-ligand [11C]ME@HAPTHI

Cited by 11 publications

References 43 publications

An experimental model of Braak’s pretangle proposal for the origin of Alzheimer’s disease: the role of locus coeruleus in early symptom development

An experimental model of Braak’s pretangle proposal for the origin of Alzheimer’s disease: the role of locus coeruleus in early symptom development

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements

Optimization of the Automated Synthesis of [11C]mHED—Administered and Apparent Molar Activities

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