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Imaging of α7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with [(18)F]NS14490.

Rötering S, Deuther-Conrad W, Cumming P, Donat CK, Scheunemann M, Fischer S, Xiong G, Steinbach J, Peters D, Sabri O, Bucerius J, Brust P - EJNMMI Res (2014)

Bottom Line: From these, [(18)F]NS14490 has been shown to yield reliable results in organ distribution studies; however, the radiosynthesis of [(18)F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets.The total distribution volume relative to the metabolite-corrected arterial input was 3.5 to 4.0 mL g(-1) throughout the telencephalon and was reduced to 2.6 mL g(-1) in animals treated with NS6740.In addition, evidence for specific binding in major brain arteries has been obtained. [(18)F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of α7 nAChR in brain but also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.

ABSTRACT

Background: The α7 nicotinic acetylcholine receptor (nAChR) is an important molecular target in neuropsychiatry and oncology. Development of applicable highly specific radiotracers has been challenging due to comparably low protein expression. To identify novel ligands as candidates for positron emission tomography (PET), a library of diazabicyclononane compounds was screened regarding affinity and specificity towards α7 nAChRs. From these, [(18)F]NS14490 has been shown to yield reliable results in organ distribution studies; however, the radiosynthesis of [(18)F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets.

Methods: Automated radiosynthesis of [(18)F]NS14490 has been performed by [(18)F]fluorination with the tosylate precursor in the TRACERlab™ FX F-N synthesis module (Waukesha, WI, USA). After optimization, the radiochemical yield of [(18)F]NS14490 was consistently approximately 35%, and the total synthesis time was about 90 min. The radiotracer was prepared with >92% radiochemical purity, and the specific activity at the end of the synthesis was 226 ± 68 GBq μmol(-1). PET measurements were performed in young pigs to investigate the metabolic stability and cerebral binding of [(18)F]NS14490 without and with administration of the α7 nAChR partial agonist NS6740 in baseline and blocking conditions.

Results: The total distribution volume relative to the metabolite-corrected arterial input was 3.5 to 4.0 mL g(-1) throughout the telencephalon and was reduced to 2.6 mL g(-1) in animals treated with NS6740. Assuming complete blockade, this displacement indicated a binding potential (BPND) of approximately 0.5 in the brain of living pigs. In addition, evidence for specific binding in major brain arteries has been obtained.

Conclusion: [(18)F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of α7 nAChR in brain but also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.

No MeSH data available.


Related in: MedlinePlus

Time-activity curves obtained during PET experiments. (A) The metabolite-corrected plasma samples. (B) Those from measurement of the whole brain and hippocampus of individual piglets. Experiments were performed under baseline (n = 4) and blocking conditions (n = 3, inset). Values are means ± S.D.
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Figure 3: Time-activity curves obtained during PET experiments. (A) The metabolite-corrected plasma samples. (B) Those from measurement of the whole brain and hippocampus of individual piglets. Experiments were performed under baseline (n = 4) and blocking conditions (n = 3, inset). Values are means ± S.D.

Mentions: [18F]NS14490 was used in dynamic PET studies in juvenile pigs. The plasma input functions under baseline and blocking conditions are shown in Figure 3A. They were corrected for the presence of radiolabelled metabolites investigated in plasma samples taken at 4, 16, 30, 60 and 120 min p.i. On average, 89% ± 3% of the radioactivity was extracted by plasma protein precipitation. Chromatographic analysis showed a spectrum of four radiometabolites (Figure 4, inset), all of them more hydrophilic than [18F]NS14490. The absence of significant cranial uptake suggests that [18F]NS14490 is not defluorinated in the pig.


Imaging of α7 nicotinic acetylcholine receptors in brain and cerebral vasculature of juvenile pigs with [(18)F]NS14490.

Rötering S, Deuther-Conrad W, Cumming P, Donat CK, Scheunemann M, Fischer S, Xiong G, Steinbach J, Peters D, Sabri O, Bucerius J, Brust P - EJNMMI Res (2014)

Time-activity curves obtained during PET experiments. (A) The metabolite-corrected plasma samples. (B) Those from measurement of the whole brain and hippocampus of individual piglets. Experiments were performed under baseline (n = 4) and blocking conditions (n = 3, inset). Values are means ± S.D.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4129469&req=5

Figure 3: Time-activity curves obtained during PET experiments. (A) The metabolite-corrected plasma samples. (B) Those from measurement of the whole brain and hippocampus of individual piglets. Experiments were performed under baseline (n = 4) and blocking conditions (n = 3, inset). Values are means ± S.D.
Mentions: [18F]NS14490 was used in dynamic PET studies in juvenile pigs. The plasma input functions under baseline and blocking conditions are shown in Figure 3A. They were corrected for the presence of radiolabelled metabolites investigated in plasma samples taken at 4, 16, 30, 60 and 120 min p.i. On average, 89% ± 3% of the radioactivity was extracted by plasma protein precipitation. Chromatographic analysis showed a spectrum of four radiometabolites (Figure 4, inset), all of them more hydrophilic than [18F]NS14490. The absence of significant cranial uptake suggests that [18F]NS14490 is not defluorinated in the pig.

Bottom Line: From these, [(18)F]NS14490 has been shown to yield reliable results in organ distribution studies; however, the radiosynthesis of [(18)F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets.The total distribution volume relative to the metabolite-corrected arterial input was 3.5 to 4.0 mL g(-1) throughout the telencephalon and was reduced to 2.6 mL g(-1) in animals treated with NS6740.In addition, evidence for specific binding in major brain arteries has been obtained. [(18)F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of α7 nAChR in brain but also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Permoserstr. 15, Leipzig 04318, Germany.

ABSTRACT

Background: The α7 nicotinic acetylcholine receptor (nAChR) is an important molecular target in neuropsychiatry and oncology. Development of applicable highly specific radiotracers has been challenging due to comparably low protein expression. To identify novel ligands as candidates for positron emission tomography (PET), a library of diazabicyclononane compounds was screened regarding affinity and specificity towards α7 nAChRs. From these, [(18)F]NS14490 has been shown to yield reliable results in organ distribution studies; however, the radiosynthesis of [(18)F]NS14490 required optimization and automation to obtain the radiotracer in quantities allowing dynamic PET studies in piglets.

Methods: Automated radiosynthesis of [(18)F]NS14490 has been performed by [(18)F]fluorination with the tosylate precursor in the TRACERlab™ FX F-N synthesis module (Waukesha, WI, USA). After optimization, the radiochemical yield of [(18)F]NS14490 was consistently approximately 35%, and the total synthesis time was about 90 min. The radiotracer was prepared with >92% radiochemical purity, and the specific activity at the end of the synthesis was 226 ± 68 GBq μmol(-1). PET measurements were performed in young pigs to investigate the metabolic stability and cerebral binding of [(18)F]NS14490 without and with administration of the α7 nAChR partial agonist NS6740 in baseline and blocking conditions.

Results: The total distribution volume relative to the metabolite-corrected arterial input was 3.5 to 4.0 mL g(-1) throughout the telencephalon and was reduced to 2.6 mL g(-1) in animals treated with NS6740. Assuming complete blockade, this displacement indicated a binding potential (BPND) of approximately 0.5 in the brain of living pigs. In addition, evidence for specific binding in major brain arteries has been obtained.

Conclusion: [(18)F]NS14490 is not only comparable to other preclinically investigated PET radiotracers for imaging of α7 nAChR in brain but also could be a potential PET radiotracer for imaging of α7 nAChR in vulnerable plaques of diseased vessels.

No MeSH data available.


Related in: MedlinePlus