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

Stehouwer, Jeffrey S.; Goodman, Mark M.

doi:10.1016/j.cpet.2009.05.006

Cited by 19 publications

(19 citation statements)

References 280 publications

(253 reference statements)

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“…A number of radiotracers have been developed to estimate the concentration of NET [12, 13]. However, the number of tracers relevant to the human brain has been limited.…”

Section: Introductionmentioning

confidence: 99%

Compartmental modeling of [11C]MENET binding to the norepinephrine transporter in the healthy human brain

Adhikarla

Zeng

Votaw

et al. 2016

Nuclear Medicine and Biology

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Introduction Dysregulation of the noradrenergic system has been implicated in a number of neurological conditions such as Parkinson’s and Alzheimer’s. [11C]MENET is a novel PET radiotracer with high affinity and selectivity for the norepinephrine transporter. The applicability of different kinetic models on [11C]MENET PET image quantification in healthy population are evaluated. Methods Six healthy volunteers (mean age: 54 years) were recruited for the study, five of whom underwent arterial sampling for measurement of the input function. Ninety minute dynamic PET scans were obtained on a high resolution research tomograph with 15 mCi of [11C]MENET injected at the scan start time. Regions of interest were delineated on the PET scan aided by the corresponding MRI image for anatomical guidance. Distribution volumes and their ratios (DVRs) with respect to the occipital reference tissue were calculated using the full arterial model (FAM), the simplified reference tissue model (SRTM) and the multilinear reference tissue model (MRTM2). Results Among the FAMs, the single-tissue model was found to be statistically superior to the two-tissue model. [11C]MENET focal uptake was observed in the NET-rich regions of the brainstem and subcortical regions including the thalamus, locus cereleus and the raphe nuclei. Highest DVRs were observed in the locus cereleus (mean ± standard deviation: 1.39 ± 0.25) and red nucleus (1.35 ± 0.25). DVRs of the thalamus were in good agreement between FAM (1.26 ± 0.13), SRTM (1.23 ± 0.15) and MRTM2 (1.21 ± 0.14). Comparing the FAM to the SRTM and MRTM2, DVRs were underestimated in the thalamus by 3% and 4% on average, respectively. Conclusion The single-tissue compartmental model was sufficient in describing the [11C]MENET kinetics in the healthy human brain. SRTM and MRTM2 present themselves as attractive options for estimating NET DVR using an occipital reference region.

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“…A number of radiotracers have been developed to estimate the concentration of NET [12, 13]. However, the number of tracers relevant to the human brain has been limited.…”

Section: Introductionmentioning

confidence: 99%

Compartmental modeling of [11C]MENET binding to the norepinephrine transporter in the healthy human brain

Adhikarla

Zeng

Votaw

et al. 2016

Nuclear Medicine and Biology

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“…Iobenguane and guanethidine are substrates for the norepinephrine transporter (NET) and accumulate by the uptake 1 mechanism into presynaptic nerve endings. Unlike norepinephrine, these drugs are protonated under physiologic conditions; therefore, they do not cross the blood-brain barrier and in vivo uptake is limited primarily to systemic neuronal tissue (2,3). In this paradigm, with chronic administration excess iobenguane can inhibit the neuroendocrine response in hypertensive patients, but with intravenous administration it can cause a hypertensive response often identified as iobenguane-associated adverse events.…”

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confidence: 99%

Phase-1 Clinical Trial Results of High-Specific-Activity Carrier-Free ¹²³I-Iobenguane

Chin

Kronauge²,

Femia³

et al. 2014

J Nucl Med

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A first-in-human phase 1 clinical study was performed on 12 healthy adults with a high-specific-activity carrier-free formulation of 123 Iiobenguane. Clinical data are presented on the behavior of this receptor-targeting imaging agent. Methods: Whole-body and thoracic planar and SPECT imaging were performed over 48 h for calculation of tissue radiation dosimetry and for evaluation of clinical safety and efficacy. Results: A reference clinical imaging database acquired over time for healthy men and women injected with highspecific-activity 123 I-iobenguane showed organ distribution and whole-body retention similar to those of conventional 123 I-iobenguane. The heart-to-mediastinum ratios for the high-specific-activity formulation were statistically higher than for conventional formulations, and the predicted radiation dosimetry estimations for some organs varied significantly from those based on animal distributions. Conclusion: Human normal-organ kinetics, radiation dosimetry, clinical safety, and imaging efficacy provide compelling evidence for the use of high-specific-activity 123 I-iobenguane.Key Words: iobenguane 123 I; MIBG; human dosimetry; high specific activity; human distribution J Nucl Med 2014; 55: 765-771 DOI: 10.2967/jnumed.113.124057 Iobenguane,ormet aiodobenzylguanidine (MIBG), is a guanethidine derivative functionally resembling norepinephrine. The drug guanethidine was developed in 1960 and was once a mainstay for the treatment of hypertension (1). It is no longer used in the United States; however, it is still licensed in some countries for the rapid control of blood pressure in a hypertensive emergency and as an intravenous nerve-blocking agent to treat chronic regional pain. Iobenguane and guanethidine are substrates for the norepinephrine transporter (NET) and accumulate by the uptake 1 mechanism into presynaptic nerve endings. Unlike norepinephrine, these drugs are protonated under physiologic conditions; therefore, they do not cross the blood-brain barrier and in vivo uptake is limited primarily to systemic neuronal tissue (2,3). In this paradigm, with chronic administration excess iobenguane can inhibit the neuroendocrine response in hypertensive patients, but with intravenous administration it can cause a hypertensive response often identified as iobenguane-associated adverse events.In healthy adults, the tissue density of systemic NET receptors is highest in the presynaptic neurons innervating myocytes (4). The accumulation of iobenguane in myocardial tissue is also dictated by the high fraction of aortic blood flow that enters the coronary arteries. This physiology constitutes an ideal molecular targeting mechanism for diagnosis of various cardiac diseases, including heart failure, heart transplant rejection, ischemic heart disease, dysautonomia, and drug-induced cardiotoxicity, as well as cardiac neuropathy related to diabetes mellitus and Parkinson disease (5-7). If a substantial fraction of the receptors are occupied by nonradioactive substrates, the overall uptake of radioactiv...

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“…A preferred method for measurement of target occupancy for CNS acting drugs is positron emission tomography (PET). PET imaging of a number of GPCRs, including dopamine, serotonin and opioid receptors, has been used successfully to examine the contribution of these receptors to human neurological diseases [116]; however, similar success stories for ion channels are still pending. The use of PET to measure drug occupancy at the site of action requires a high affinity tracer that is cleared quickly and a sufficient density of receptor sites on the tissue of interest.…”

Section: Structure-based Drug Designmentioning

confidence: 99%

Ion channel drug discovery: challenges and future directions

Wickenden

Priest

Erdemli³

2012

Future Medicinal Chemistry

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Ion channels are targets of many therapeutically useful agents, and worldwide sales of ion channel-targeted drugs are estimated to be approximately US$12 billion. Nevertheless, considering that over 400 genes encoding ion channel subunits have been identified, ion channels remain significantly under-exploited as therapeutic targets. This is at least partly due to limitations in high-throughput assay technologies that support screening and lead optimization. Will the recent developments in automated electrophysiology rectify this situation? What are the other major limitations and can they be overcome? In this article, we review the status of ion channel drug discovery, discuss current challenges and propose alternative approaches that may facilitate the discovery of new drugs in the future.

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

Cited by 19 publications

References 280 publications

Compartmental modeling of [11C]MENET binding to the norepinephrine transporter in the healthy human brain

Compartmental modeling of [11C]MENET binding to the norepinephrine transporter in the healthy human brain

Phase-1 Clinical Trial Results of High-Specific-Activity Carrier-Free ¹²³I-Iobenguane

Ion channel drug discovery: challenges and future directions

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

Cited by 19 publications

References 280 publications

Compartmental modeling of [11C]MENET binding to the norepinephrine transporter in the healthy human brain

Compartmental modeling of [11C]MENET binding to the norepinephrine transporter in the healthy human brain

Phase-1 Clinical Trial Results of High-Specific-Activity Carrier-Free 123I-Iobenguane

Ion channel drug discovery: challenges and future directions

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Phase-1 Clinical Trial Results of High-Specific-Activity Carrier-Free ¹²³I-Iobenguane