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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.

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(a) Color codedPET images show accumulation of [18F]3 inthe selected five coronal slices of the monkey brainat the time point 5–15 min after the injection of radioactivity.These images show the highest accumulation of [18F]3 in the caudate, putamen, thalamus, and several corticalareas. (b) Fused PET and MR images from (a) and (c). (c) T1-weightedcoronal MR images show the anatomical structures of selected brainareas. (n = 1) 189 MBq [18F]3 (37 ng/kg) was injected.
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fig4: (a) Color codedPET images show accumulation of [18F]3 inthe selected five coronal slices of the monkey brainat the time point 5–15 min after the injection of radioactivity.These images show the highest accumulation of [18F]3 in the caudate, putamen, thalamus, and several corticalareas. (b) Fused PET and MR images from (a) and (c). (c) T1-weightedcoronal MR images show the anatomical structures of selected brainareas. (n = 1) 189 MBq [18F]3 (37 ng/kg) was injected.

Mentions: Afterthe characterization of [18F]3 inrats studies, combined PET–MRI studies showed similar resultsin the monkey brain with high accumulation of [18F]3 in the regions such as the striatum, thalamus, hippocampus,and cerebellum where previous literature has reported high expressionof mGlu4 (Figure 4a).4,15 T1-weighed MRI study (Figure 4c) and fusedPET–MRI studies (Figure 4b) illustratedanatomical details and the regional distribution of [18F]3.


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)

(a) Color codedPET images show accumulation of [18F]3 inthe selected five coronal slices of the monkey brainat the time point 5–15 min after the injection of radioactivity.These images show the highest accumulation of [18F]3 in the caudate, putamen, thalamus, and several corticalareas. (b) Fused PET and MR images from (a) and (c). (c) T1-weightedcoronal MR images show the anatomical structures of selected brainareas. (n = 1) 189 MBq [18F]3 (37 ng/kg) was injected.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: (a) Color codedPET images show accumulation of [18F]3 inthe selected five coronal slices of the monkey brainat the time point 5–15 min after the injection of radioactivity.These images show the highest accumulation of [18F]3 in the caudate, putamen, thalamus, and several corticalareas. (b) Fused PET and MR images from (a) and (c). (c) T1-weightedcoronal MR images show the anatomical structures of selected brainareas. (n = 1) 189 MBq [18F]3 (37 ng/kg) was injected.
Mentions: Afterthe characterization of [18F]3 inrats studies, combined PET–MRI studies showed similar resultsin the monkey brain with high accumulation of [18F]3 in the regions such as the striatum, thalamus, hippocampus,and cerebellum where previous literature has reported high expressionof mGlu4 (Figure 4a).4,15 T1-weighed MRI study (Figure 4c) and fusedPET–MRI studies (Figure 4b) illustratedanatomical details and the regional distribution of [18F]3.

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