TY - JOUR
T1 - Synthesis and Evaluation of a New 18 F-Labeled Radiotracer for Studying the GABA B Receptor in the Mouse Brain
AU - Naik, Ravi
AU - Valentine, Heather
AU - Dannals, Robert F.
AU - Wong, Dean F.
AU - Horti, Andrew G.
N1 - Funding Information:
*Phone: 410-614-5130. E-mail: ahorti1@jhmi.edu. ORCID Andrew G. Horti: 0000-0003-2290-488X Author Contributions R.N. synthesized all unlabeled compounds. A.G.H. and D.F.W. designed the experiments. A.G.H. and D.F.W. analyzed the animal data. A.G.H. and R.N. were involved in writing the manuscript. A.G.H. and R.F.D. were involved in radiosynthesis of GABAB radiotracer. H.V., A.G.H., and R.N. were involved in the mouse studies. Funding This research was supported in part by SFARI (Simon Foundation Autism Research Initiative) grant (D.F.W., A.G.H.) and Division of Nuclear Medicine and Molecular Imaging. Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/6/20
Y1 - 2018/6/20
N2 - New GABA B agonists, fluoropyridyl ether analogues of baclofen, have been synthesized as potential PET radiotracers. The compound with highest inhibition binding affinity as well as greatest agonist response, (R)-4-amino-3-(4-chloro-3-((2-fluoropyridin-4-yl)methoxy)phenyl)butanoic acid (1b), was radiolabeled with 18 F with good radiochemical yield, high radiochemical purity, and high molar radioactivity. The regional brain distribution of the radiolabeled (R)-4-amino-3-(4-chloro-3-((2-[ 18 F]fluoropyridin-4-yl)methoxy)phenyl)butanoic acid, [ 18 F]1b, was studied in CD-1 male mice. The study demonstrated that [ 18 F]1b enters the mouse brain (1% ID/g tissue). The accumulation of [ 18 F]1b in the mouse brain was inhibited (35%) by preinjection of GABA B agonist 1a, suggesting that the radiotracer brain uptake is partially mediated by GABA B receptors. The presented data demonstrate a feasibility of imaging of GABA B receptors in rodents and justify further development of GABA B PET tracers with improved specific binding and greater blood-brain barrier permeability.
AB - New GABA B agonists, fluoropyridyl ether analogues of baclofen, have been synthesized as potential PET radiotracers. The compound with highest inhibition binding affinity as well as greatest agonist response, (R)-4-amino-3-(4-chloro-3-((2-fluoropyridin-4-yl)methoxy)phenyl)butanoic acid (1b), was radiolabeled with 18 F with good radiochemical yield, high radiochemical purity, and high molar radioactivity. The regional brain distribution of the radiolabeled (R)-4-amino-3-(4-chloro-3-((2-[ 18 F]fluoropyridin-4-yl)methoxy)phenyl)butanoic acid, [ 18 F]1b, was studied in CD-1 male mice. The study demonstrated that [ 18 F]1b enters the mouse brain (1% ID/g tissue). The accumulation of [ 18 F]1b in the mouse brain was inhibited (35%) by preinjection of GABA B agonist 1a, suggesting that the radiotracer brain uptake is partially mediated by GABA B receptors. The presented data demonstrate a feasibility of imaging of GABA B receptors in rodents and justify further development of GABA B PET tracers with improved specific binding and greater blood-brain barrier permeability.
KW - GABAB receptor
KW - PET
KW - autism
KW - blood-brain barrier permeability
KW - radiotracer
UR - http://www.scopus.com/inward/record.url?scp=85048747326&partnerID=8YFLogxK
U2 - 10.1021/acschemneuro.8b00038
DO - 10.1021/acschemneuro.8b00038
M3 - Article
C2 - 29498831
AN - SCOPUS:85048747326
SN - 1948-7193
VL - 9
SP - 1453
EP - 1461
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 6
ER -