Synthesis, characterization, and monkey positron emission tomography (PET) studies of [18F]Y1-973, a PET tracer for the neuropeptide Y Y1 receptor

Hostetler, Eric D.; Sanabria-Bohórquez, Sandra M.; Fan, Hong; Zeng, Zhizhen; Gantert, Liza; Williams, M. A.; Miller, Patricia; O’Malley, Stacey; Kameda, Minoru; Ando, Makoto; Sato, Nagaaki; Ozaki, Satoshi; Tokita, Shigeru; Ohta, Hisashi; Williams, David L.; Sur, Cyrille; Cook, Jacquelynn J.; Burns, H. Donald; Hargreaves, Richard

doi:10.1016/j.neuroimage.2010.11.014

Cited by 31 publications

(30 citation statements)

References 22 publications

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“…The signal for NPY1R mRNA was strong and widespread in several cortical areas, consistent with prior reports in humans (46–48). While there are no published studies describing the mRNA distribution of NPY1R in the rhesus brain, a PET and in vitro autoradiography study employing 18 F-Y1-973 revealed patterns of receptor localization that are in general agreement with our observations (49). The widespread distribution throughout the cortex is also seen in the rat and mouse brain where NPY1R mRNA is detectable in essentially all cortical fields (50).…”

Section: Discussionsupporting

confidence: 90%

Neuropeptide Y Receptor Gene Expression in the Primate Amygdala Predicts Anxious Temperament and Brain Metabolism

Roseboom¹,

Nanda²,

Fox

et al. 2014

Biological Psychiatry

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Background Anxious temperament (AT) is identifiable early in life and predicts the later development of anxiety disorders and depression. Neuropeptide Y (NPY) is a putative endogenous anxiolytic neurotransmitter that adaptively regulates responses to stress and may confer resilience to stress-related psychopathology. Using a well-validated non-human primate model of AT, we examined expression of the NPY system in the central nucleus (Ce) of the amygdala, a critical neural substrate for extreme anxiety. Methods In twenty-four young rhesus monkeys, we measured Ce mRNA levels of all members of the NPY system that are detectable in the Ce using quantitative real time polymerase chain reaction (qRT-PCR). We then examined the relationship between these mRNA levels and both AT expression and brain metabolism. Results Lower mRNA levels of NPY receptor 1 (NPY1R) and NPY receptor 5 (NPY5R), but not NPY or NPY receptor 2 (NPY2R) in the Ce predicted elevated AT; mRNA levels for NPY1R and NPY5R in the motor cortex were not related to AT. In situ hybridization analysis provided for the first time a detailed description of NPY1R and NPY5R mRNA distribution in the rhesus amygdala and associated regions. Lastly, mRNA levels for these two receptors in the Ce predicted metabolic activity in several regions that have the capacity to regulate the Ce. Conclusion Decreased NPY signaling in the Ce may contribute to the altered metabolic activity that is a component of the neural substrate underlying AT. This suggests that enhancement of NPY signaling may reduce the risk to develop psychopathology.

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Section: Discussionsupporting

confidence: 90%

Neuropeptide Y Receptor Gene Expression in the Primate Amygdala Predicts Anxious Temperament and Brain Metabolism

Roseboom¹,

Nanda²,

Fox

et al. 2014

Biological Psychiatry

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“…The tracer showed a IC 50 of 0.13 nM for human Y1-R, a log P of 3.2 ( Table 2) and a P-gp ratio of 1.3.These properties meet the requirements to peptide receptor ligands with K i < 0.5 nM, log P < 3.5; and P-gp ratio < 3, which have been declared to be a generally necessary feature [120,124]. The authors emphasize the favourable kinetics in the brain, an accumulation in the striatum at 30 min with a binding potential of 1.7 and a high uptake also in cortical regions, whereas the uptake was moderate in thalamus and lowest in cerebellum as can be expected for a NPY1-R ligand Y1-718 (IC 50 17 nM) (19) was used for investigation of reversibility and specifity of Y1-973 binding [124].…”

Section: Non-peptide Ligands Of Npy Receptorsmentioning

confidence: 60%

“…Keller et al [122,123] and Weiss et al [124] recommended the synthesis of ligands using substitution of argininamide type compounds with an acylguanidine entity at the guanidine as in BIBP 3226 (15) or the acylation of the guanidine group with propionic acid as in UR-MK114 (16) (Figure 3(a)) leading to high affinity (K d 1.2 nM) and selectivity for NPY1-Rs. Additionally, these antagonists exhibit an excellent long-term stability and only slow radiolysis if storage is performed as TFA salt in ethanol.…”

Section: Non-peptide Ligands Of Npy Receptorsmentioning

confidence: 99%

“…Recently, the presentation of the 18 F-labeled NPY1 antagonist Y1-973 (18) (Figure 3(b)) [124] was a breakthrough in NPY1 PET imaging. The tracer showed a IC 50 of 0.13 nM for human Y1-R, a log P of 3.2 ( Table 2) and a P-gp ratio of 1.3.These properties meet the requirements to peptide receptor ligands with K i < 0.5 nM, log P < 3.5; and P-gp ratio < 3, which have been declared to be a generally necessary feature [120,124].…”

Section: Non-peptide Ligands Of Npy Receptorsmentioning

confidence: 99%

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Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Pissarek¹,

Disko²

2013

WJNS

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Hypothalamic receptors for neuropeptide Y, melaninconcentrating hormone, melanocortins and orexins/ hypocretins as well as for the downstream signaling corticotrophic factor have been discussed broadly for their influence on food intake and reward but also on several psychiatric disorders. For the development of non-peptide ligands for the in vivo detection of alterations in density and affinity of such G-protein coupled (GPCRs) peptide receptors the requirements to affinity and pharmacokinetics have been shifted to thresholds markedly distict from classical GPCRs to dissociation constants < 0.5 nM, partition coefficients log P < 3.5 and transcellular transport ratios, e.g. for the permeability glycoprotein transporter, below 3. Nevertheless, a multitude of compounds has been reported originally as potential therapeutics in the treatment of obesity among which some are suitable candidates for labeling as PET or SPECT-tracers providing receptor affinities even below 0.1 nM. These could be unique tools not only for better understanding of the mechanism of obesity but also for investigations of extrahypothalamic role of "feeding receptors" at the interface between neuroendocrine and mental diseases.

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“…15. Notably, for the σ 1 receptor, as for metabotropic glutamate receptor 1 (mGluR1) [59] and the GABA A receptor [180] , the cerebellum is among the regions with the highest expression and cannot be used as a reference region in this case. The ratio between the region with lowest radiotracer accumulation (olfactory bulb) and that with highest accumulation (facial nucleus) was chosen for the estimation of specifi c receptor binding.…”

mentioning

confidence: 99%

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

2014

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Positron emission tomography (PET) is an in vivo molecular imaging tool which is widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. PET uses biomolecules as probes which are labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. Fluorine-18 is a radionuclide routinely used in the radiolabeling of neuroreceptor ligands for PET because of its favorable half-life of 109.8 min. The delivery of such radiotracers into the brain provides images of transport, metabolic, and neurotransmission processes on the molecular level. After a short introduction into the principles of PET, this review mainly focuses on the strategy of radiotracer development bridging from basic science to biomedical application. Successful radiotracer design as described here provides molecular probes which not only are useful for imaging of human brain diseases, but also allow molecular neuroreceptor imaging studies in various small-animal models of disease, including geneticallyengineered animals. Furthermore, they provide a powerful tool for in vivo pharmacology during the process of pre-clinical drug development to identify new drug targets, to investigate pathophysiology, to discover potential drug candidates, and to evaluate the pharmacokinetics and pharmacodynamics of drugs in vivo.Keywords: Alzheimer's disease; autoradiography; blood-brain barrier; brain tumor; cholinergic system; kinetic modeling; metabolism; molecular imaging; neurodegeneration; positron emission tomography; precursor; psychiatric disorder; radiotracer; sigma receptor ·Review· IntroductionPositron emission tomography (PET) is an in vivo molecular imaging tool widely used in nuclear medicine for early diagnosis and treatment follow-up of many brain diseases. Positron-emitting radionuclide-labeled substances allow the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems by highly sensitive coincidence-detection [1] . This is based on 511 keV photons (gamma radiation) originating from positronelectron annihilation. PET differs in that aspect from other modalities such as single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical imaging, and ultrasound. Because of their high sensitivity (~10 -9 to 10 -12 M) PET and SPECT offer advantages over the other methods. Therefore, in the past, they were the only modalities that allowed noninvasive imaging of biochemical receptor sites. Nowadays, the other imaging modalities compete in that aspect although precise absolute quantitation in terms of biochemical parameters has not been achieved yet. fusion accuracy, provides an advanced diagnostic tool and research platform [2,3] .PET and SPECT use biomolecules as probes, labeled with radionuclides of short half-lives, synthesized prior to the imaging studies. These probes are called radiotracers. According to the concept developed by George ...

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Synthesis, characterization, and monkey positron emission tomography (PET) studies of [18F]Y1-973, a PET tracer for the neuropeptide Y Y1 receptor

Cited by 31 publications

References 22 publications

Neuropeptide Y Receptor Gene Expression in the Primate Amygdala Predicts Anxious Temperament and Brain Metabolism

Neuropeptide Y Receptor Gene Expression in the Primate Amygdala Predicts Anxious Temperament and Brain Metabolism

Non-peptide ligands in the characterization of peptide receptors at the interface between neuroendocrine and mental diseases

Development of 18F-labeled radiotracers for neuroreceptor imaging with positron emission tomography

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