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

(a)TACs derived from the rat brain PET images [18F]3 (n = 7). (b) mGlu4 blocking studies demonstratedreduced uptake in the brain regions by 10–20%, while mGlu5blocking agents displayed minimal blocking effect indicating goodselectivity to mGlu4. Tissue uptake was calculated as area under TACexpressed as (% dose/cc) × min: Str = striatum, Hipp = hippocampus,Thal = thalamus, Cort = cortex, Cereb = cerebellum, WB = whole brain.Shown are results from baseline studies (n = 7),mGlu4 (2) blocking studies (n = 4),and mGlu5 (MTEP) blocking studies (n = 3). (c) Percentageof [18F]3 in the plasma over time. (n = 2).
© Copyright Policy
Related In: Results  -  Collection

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

fig3: (a)TACs derived from the rat brain PET images [18F]3 (n = 7). (b) mGlu4 blocking studies demonstratedreduced uptake in the brain regions by 10–20%, while mGlu5blocking agents displayed minimal blocking effect indicating goodselectivity to mGlu4. Tissue uptake was calculated as area under TACexpressed as (% dose/cc) × min: Str = striatum, Hipp = hippocampus,Thal = thalamus, Cort = cortex, Cereb = cerebellum, WB = whole brain.Shown are results from baseline studies (n = 7),mGlu4 (2) blocking studies (n = 4),and mGlu5 (MTEP) blocking studies (n = 3). (c) Percentageof [18F]3 in the plasma over time. (n = 2).

Mentions: The characterizationof [18F]3 was first conducted with rat (maleSprague–Dawley) studies. These studies demonstrated that [18F]3 crossed BBB and occupied brain areas knownto express mGlu4. Time−activity curves (TACs) showedfast uptake and washout in different brain regions within 20 min (Figure 3a). These results are similar to our previous PETstudies with [11C]1.17


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)TACs derived from the rat brain PET images [18F]3 (n = 7). (b) mGlu4 blocking studies demonstratedreduced uptake in the brain regions by 10–20%, while mGlu5blocking agents displayed minimal blocking effect indicating goodselectivity to mGlu4. Tissue uptake was calculated as area under TACexpressed as (% dose/cc) × min: Str = striatum, Hipp = hippocampus,Thal = thalamus, Cort = cortex, Cereb = cerebellum, WB = whole brain.Shown are results from baseline studies (n = 7),mGlu4 (2) blocking studies (n = 4),and mGlu5 (MTEP) blocking studies (n = 3). (c) Percentageof [18F]3 in the plasma over time. (n = 2).
© Copyright Policy
Related In: Results  -  Collection

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

fig3: (a)TACs derived from the rat brain PET images [18F]3 (n = 7). (b) mGlu4 blocking studies demonstratedreduced uptake in the brain regions by 10–20%, while mGlu5blocking agents displayed minimal blocking effect indicating goodselectivity to mGlu4. Tissue uptake was calculated as area under TACexpressed as (% dose/cc) × min: Str = striatum, Hipp = hippocampus,Thal = thalamus, Cort = cortex, Cereb = cerebellum, WB = whole brain.Shown are results from baseline studies (n = 7),mGlu4 (2) blocking studies (n = 4),and mGlu5 (MTEP) blocking studies (n = 3). (c) Percentageof [18F]3 in the plasma over time. (n = 2).
Mentions: The characterizationof [18F]3 was first conducted with rat (maleSprague–Dawley) studies. These studies demonstrated that [18F]3 crossed BBB and occupied brain areas knownto express mGlu4. Time−activity curves (TACs) showedfast uptake and washout in different brain regions within 20 min (Figure 3a). These results are similar to our previous PETstudies with [11C]1.17

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