Limits...
Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4).

Kil KE, Poutiainen P, Zhang Z, Zhu A, Choi JK, Jokivarsi K, Brownell AL - J. Med. Chem. (2014)

Bottom Line: Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F.In vivo imaging studies in a monkey showed that the radiotracer quickly penetrated the brain with the highest accumulation in the brain areas known to express mGlu4.Despite some unfavorable radiotracer properties like fast washout in rodent studies, [(18)F]3 is the first (18)F-labeled mGlu4 radioligand, which can be further modified to improve pharmacokinetics and brain penetrability for future human studies.

View Article: PubMed Central - PubMed

Affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital , Charlestown, Massachusetts 02129, United States.

ABSTRACT
Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F. When finally formulated in 0.1 M citrate buffer (pH 4) with 10% ethanol, the specific activity of [(18)F]3 at the end of synthesis (EOS) was 233.5 ± 177.8 GBq/μmol (n = 4). The radiochemical yield of [(18)F]3 was 16.4 ± 4.8% (n = 4), and the purity was over 98%. In vivo imaging studies in a monkey showed that the radiotracer quickly penetrated the brain with the highest accumulation in the brain areas known to express mGlu4. Despite some unfavorable radiotracer properties like fast washout in rodent studies, [(18)F]3 is the first (18)F-labeled mGlu4 radioligand, which can be further modified to improve pharmacokinetics and brain penetrability for future human studies.

Show MeSH

Related in: MedlinePlus

Representative mGlu4 PAMs from N-phenyl-2-picolinamidesand the corresponding phthalimide derivatives.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4230996&req=5

fig1: Representative mGlu4 PAMs from N-phenyl-2-picolinamidesand the corresponding phthalimide derivatives.

Mentions: Aimed at improving thepotency of the previousPET ligand, we have looked for a new type of mGlu4 PAMwith improved properties for developing a new PET tracer. In recentyears, a series of phthalimide derivatives of N-phenyl-2-picolinamideshave been developed as mGlu4 PAMs by the Merck ResearchLaboratory and Vanderbilt University.20,21 Four representativecompounds (3–6) from this seriesare shown in Figure 1. ML182 (6) was a saturated version of the phthalimide, which proved to beorally active in the haloperidol induced catalepsy model, a well-establishedantiparkinsonian model. It was also shown that compounds 3 (hEC50 = 50.4 nM; IC50 = 36 nM), 4 (hEC50 = 43.6 nM; IC50 = 11 nM), and 5 (hEC50 = 101 nM; IC50 = 12 nM) hadenhanced activity compared with 1 (hEC50 =240 nM) and gave excellent binding affinity (depicted as the IC50 value) to mGlu4. Compound 4 wasradiolabeled with tritium as a tool compound for in vitro studies.20 When the structures of 3–5 were checked, it was determined that the picolinamide (leftside) was critical for the mGlu4 potency,16 and the phthalimide group at the 4-position on the phenylring enhanced potency compared to 1. In addition, althoughboth the chloro- and bromo-substitutions at the 3-position of thephenyl ring (4 and 5) gave good bindingaffinities, the chloro-substitution was more favorable, since thebromo-substitution increased molecular weight as well as clogP valuebut not the potency at mGlu4. Because of their promisingaffinity to mGlu4, we have synthesized four phthalimidederivatives including 3 and 4 as well astheir analogs 7 and 8 for further studies. 3, 4, 7, and 8 onlydiffer in the halide and methyl groups on the phenyl ring of the phthalimide,which may offer an appropriate site for labeling the correspondingpositron emitting radionuclides such as fluorine-18, carbon-11, bromine-76,and iodine-124, respectively.


Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4).

Kil KE, Poutiainen P, Zhang Z, Zhu A, Choi JK, Jokivarsi K, Brownell AL - J. Med. Chem. (2014)

Representative mGlu4 PAMs from N-phenyl-2-picolinamidesand the corresponding phthalimide derivatives.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230996&req=5

fig1: Representative mGlu4 PAMs from N-phenyl-2-picolinamidesand the corresponding phthalimide derivatives.
Mentions: Aimed at improving thepotency of the previousPET ligand, we have looked for a new type of mGlu4 PAMwith improved properties for developing a new PET tracer. In recentyears, a series of phthalimide derivatives of N-phenyl-2-picolinamideshave been developed as mGlu4 PAMs by the Merck ResearchLaboratory and Vanderbilt University.20,21 Four representativecompounds (3–6) from this seriesare shown in Figure 1. ML182 (6) was a saturated version of the phthalimide, which proved to beorally active in the haloperidol induced catalepsy model, a well-establishedantiparkinsonian model. It was also shown that compounds 3 (hEC50 = 50.4 nM; IC50 = 36 nM), 4 (hEC50 = 43.6 nM; IC50 = 11 nM), and 5 (hEC50 = 101 nM; IC50 = 12 nM) hadenhanced activity compared with 1 (hEC50 =240 nM) and gave excellent binding affinity (depicted as the IC50 value) to mGlu4. Compound 4 wasradiolabeled with tritium as a tool compound for in vitro studies.20 When the structures of 3–5 were checked, it was determined that the picolinamide (leftside) was critical for the mGlu4 potency,16 and the phthalimide group at the 4-position on the phenylring enhanced potency compared to 1. In addition, althoughboth the chloro- and bromo-substitutions at the 3-position of thephenyl ring (4 and 5) gave good bindingaffinities, the chloro-substitution was more favorable, since thebromo-substitution increased molecular weight as well as clogP valuebut not the potency at mGlu4. Because of their promisingaffinity to mGlu4, we have synthesized four phthalimidederivatives including 3 and 4 as well astheir analogs 7 and 8 for further studies. 3, 4, 7, and 8 onlydiffer in the halide and methyl groups on the phenyl ring of the phthalimide,which may offer an appropriate site for labeling the correspondingpositron emitting radionuclides such as fluorine-18, carbon-11, bromine-76,and iodine-124, respectively.

Bottom Line: Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F.In vivo imaging studies in a monkey showed that the radiotracer quickly penetrated the brain with the highest accumulation in the brain areas known to express mGlu4.Despite some unfavorable radiotracer properties like fast washout in rodent studies, [(18)F]3 is the first (18)F-labeled mGlu4 radioligand, which can be further modified to improve pharmacokinetics and brain penetrability for future human studies.

View Article: PubMed Central - PubMed

Affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital , Charlestown, Massachusetts 02129, United States.

ABSTRACT
Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F. When finally formulated in 0.1 M citrate buffer (pH 4) with 10% ethanol, the specific activity of [(18)F]3 at the end of synthesis (EOS) was 233.5 ± 177.8 GBq/μmol (n = 4). The radiochemical yield of [(18)F]3 was 16.4 ± 4.8% (n = 4), and the purity was over 98%. In vivo imaging studies in a monkey showed that the radiotracer quickly penetrated the brain with the highest accumulation in the brain areas known to express mGlu4. Despite some unfavorable radiotracer properties like fast washout in rodent studies, [(18)F]3 is the first (18)F-labeled mGlu4 radioligand, which can be further modified to improve pharmacokinetics and brain penetrability for future human studies.

Show MeSH
Related in: MedlinePlus