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Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.

Rais R, Wozniak K, Wu Y, Niwa M, Stathis M, Alt J, Giroux M, Sawa A, Rojas C, Slusher BS - PLoS ONE (2015)

Bottom Line: Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration.Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas.Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement.

View Article: PubMed Central - PubMed

Affiliation: Brain Science Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p.) administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0) but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67), cortex (AUC0-t, i.n./AUC0-t, i.p. = 46) and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3). Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies support intranasal delivery of 2-PMPA to deliver therapeutic concentrations in the brain and may facilitate its clinical development.

No MeSH data available.


Related in: MedlinePlus

Ex vivo GCP-II enzymatic activity following 2-PMPA i.n. administration.Enzyme activity was measured in olfactory bulb, cortex and cerebellum collected 1 h post dose following 30 mg/kg i.n. administration. Percent inhibition was calculated in all tissue samples relative to brain tissues collected from untreated control rats.
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pone.0131861.g005: Ex vivo GCP-II enzymatic activity following 2-PMPA i.n. administration.Enzyme activity was measured in olfactory bulb, cortex and cerebellum collected 1 h post dose following 30 mg/kg i.n. administration. Percent inhibition was calculated in all tissue samples relative to brain tissues collected from untreated control rats.

Mentions: Target engagement studies were performed by measurement of GCP-II enzymatic activity in brain tissue 1 h following i.n. 2-PMPA administration (Fig 5). There was complete (100%) inhibition of GCP-II activity measured in olfactory bulb and cortex following i.n. administration and almost complete (70% ± 5%) inhibition in the cerebellum.


Selective CNS Uptake of the GCP-II Inhibitor 2-PMPA following Intranasal Administration.

Rais R, Wozniak K, Wu Y, Niwa M, Stathis M, Alt J, Giroux M, Sawa A, Rojas C, Slusher BS - PLoS ONE (2015)

Ex vivo GCP-II enzymatic activity following 2-PMPA i.n. administration.Enzyme activity was measured in olfactory bulb, cortex and cerebellum collected 1 h post dose following 30 mg/kg i.n. administration. Percent inhibition was calculated in all tissue samples relative to brain tissues collected from untreated control rats.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494705&req=5

pone.0131861.g005: Ex vivo GCP-II enzymatic activity following 2-PMPA i.n. administration.Enzyme activity was measured in olfactory bulb, cortex and cerebellum collected 1 h post dose following 30 mg/kg i.n. administration. Percent inhibition was calculated in all tissue samples relative to brain tissues collected from untreated control rats.
Mentions: Target engagement studies were performed by measurement of GCP-II enzymatic activity in brain tissue 1 h following i.n. 2-PMPA administration (Fig 5). There was complete (100%) inhibition of GCP-II activity measured in olfactory bulb and cortex following i.n. administration and almost complete (70% ± 5%) inhibition in the cerebellum.

Bottom Line: Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration.Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas.Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement.

View Article: PubMed Central - PubMed

Affiliation: Brain Science Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America; Department of Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.

ABSTRACT
Glutamate carboxypeptidase II (GCP-II) is a brain metallopeptidase that hydrolyzes the abundant neuropeptide N-acetyl-aspartyl-glutamate (NAAG) to NAA and glutamate. Small molecule GCP-II inhibitors increase brain NAAG, which activates mGluR3, decreases glutamate, and provide therapeutic utility in a variety of preclinical models of neurodegenerative diseases wherein excess glutamate is presumed pathogenic. Unfortunately no GCP-II inhibitor has advanced clinically, largely due to their highly polar nature resulting in insufficient oral bioavailability and limited brain penetration. Herein we report a non-invasive route for delivery of GCP-II inhibitors to the brain via intranasal (i.n.) administration. Three structurally distinct classes of GCP-II inhibitors were evaluated including DCMC (urea-based), 2-MPPA (thiol-based) and 2-PMPA (phosphonate-based). While all showed some brain penetration following i.n. administration, 2-PMPA exhibited the highest levels and was chosen for further evaluation. Compared to intraperitoneal (i.p.) administration, equivalent doses of i.n. administered 2-PMPA resulted in similar plasma exposures (AUC0-t, i.n./AUC0-t, i.p. = 1.0) but dramatically enhanced brain exposures in the olfactory bulb (AUC0-t, i.n./AUC0-t, i.p. = 67), cortex (AUC0-t, i.n./AUC0-t, i.p. = 46) and cerebellum (AUC0-t, i.n./AUC0-t, i.p. = 6.3). Following i.n. administration, the brain tissue to plasma ratio based on AUC0-t in the olfactory bulb, cortex, and cerebellum were 1.49, 0.71 and 0.10, respectively, compared to an i.p. brain tissue to plasma ratio of less than 0.02 in all areas. Furthermore, i.n. administration of 2-PMPA resulted in complete inhibition of brain GCP-II enzymatic activity ex-vivo confirming target engagement. Lastly, because the rodent nasal system is not similar to humans, we evaluated i.n. 2-PMPA also in a non-human primate. We report that i.n. 2-PMPA provides selective brain delivery with micromolar concentrations. These studies support intranasal delivery of 2-PMPA to deliver therapeutic concentrations in the brain and may facilitate its clinical development.

No MeSH data available.


Related in: MedlinePlus