14 research outputs found
Effect of stereochemistry on ester hydrolysis by cholinesterases: Implications for radiotracer design
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91202/1/2580440138_ftp.pd
Design and Selection Parameters to Accelerate the Discovery of Novel Central Nervous System Positron Emission Tomography (PET) Ligands and Their Application in the Development of a Novel Phosphodiesterase 2A PET Ligand
To
accelerate the discovery of novel small molecule central nervous
system (CNS) positron emission tomography (PET) ligands, we aimed
to define a property space that would facilitate ligand design and
prioritization, thereby providing a higher probability of success
for novel PET ligand development. Toward this end, we built a database
consisting of 62 PET ligands that have successfully reached the clinic
and 15 radioligands that failed in late-stage development as negative
controls. A systematic analysis of these ligands identified a set
of preferred parameters for physicochemical properties, brain permeability,
and nonspecific binding (NSB). These preferred parameters have subsequently
been applied to several programs and have led to the successful development
of novel PET ligands with reduced resources and timelines. This strategy
is illustrated here by the discovery of the novel phosphodiesterase
2A (PDE2A) PET ligand 4-(3-[<sup>18</sup>F]Âfluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)Âphenyl]-1<i>H</i>-pyrazol-4-yl}ÂimidazoÂ[5,1-<i>f</i>]Â[1,2,4]Âtriazine,
[<sup>18</sup>F]ÂPF-05270430 (<b>5</b>)
Design and Selection Parameters to Accelerate the Discovery of Novel Central Nervous System Positron Emission Tomography (PET) Ligands and Their Application in the Development of a Novel Phosphodiesterase 2A PET Ligand
To
accelerate the discovery of novel small molecule central nervous
system (CNS) positron emission tomography (PET) ligands, we aimed
to define a property space that would facilitate ligand design and
prioritization, thereby providing a higher probability of success
for novel PET ligand development. Toward this end, we built a database
consisting of 62 PET ligands that have successfully reached the clinic
and 15 radioligands that failed in late-stage development as negative
controls. A systematic analysis of these ligands identified a set
of preferred parameters for physicochemical properties, brain permeability,
and nonspecific binding (NSB). These preferred parameters have subsequently
been applied to several programs and have led to the successful development
of novel PET ligands with reduced resources and timelines. This strategy
is illustrated here by the discovery of the novel phosphodiesterase
2A (PDE2A) PET ligand 4-(3-[<sup>18</sup>F]Âfluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)Âphenyl]-1<i>H</i>-pyrazol-4-yl}ÂimidazoÂ[5,1-<i>f</i>]Â[1,2,4]Âtriazine,
[<sup>18</sup>F]ÂPF-05270430 (<b>5</b>)
The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging
As
part of our effort in identifying phosphodiesterase (PDE) 4B-preferring
inhibitors for the treatment of central nervous system (CNS) disorders,
we sought to identify a positron emission tomography (PET) ligand
to enable target occupancy measurement in vivo. Through a systematic
and cost-effective PET discovery process, involving expression level
(<i>B</i><sub>max</sub>) and biodistribution determination,
a PET-specific structure–activity relationship (SAR) effort,
and specific binding assessment using a LC-MS/MS “cold tracer”
method, we have identified <b>8</b> (PF-06445974) as a promising
PET lead. Compound <b>8</b> has exquisite potency at PDE4B,
good selectivity over PDE4D, excellent brain permeability, and a high
level of specific binding in the “cold tracer” study.
In subsequent non-human primate (NHP) PET imaging studies, [<sup>18</sup>F]<b>8</b> showed rapid brain uptake and high target specificity,
indicating that [<sup>18</sup>F]<b>8</b> is a promising PDE4B-preferring
radioligand for clinical PET imaging
The Discovery of a Novel Phosphodiesterase (PDE) 4B-Preferring Radioligand for Positron Emission Tomography (PET) Imaging
As
part of our effort in identifying phosphodiesterase (PDE) 4B-preferring
inhibitors for the treatment of central nervous system (CNS) disorders,
we sought to identify a positron emission tomography (PET) ligand
to enable target occupancy measurement in vivo. Through a systematic
and cost-effective PET discovery process, involving expression level
(<i>B</i><sub>max</sub>) and biodistribution determination,
a PET-specific structure–activity relationship (SAR) effort,
and specific binding assessment using a LC-MS/MS “cold tracer”
method, we have identified <b>8</b> (PF-06445974) as a promising
PET lead. Compound <b>8</b> has exquisite potency at PDE4B,
good selectivity over PDE4D, excellent brain permeability, and a high
level of specific binding in the “cold tracer” study.
In subsequent non-human primate (NHP) PET imaging studies, [<sup>18</sup>F]<b>8</b> showed rapid brain uptake and high target specificity,
indicating that [<sup>18</sup>F]<b>8</b> is a promising PDE4B-preferring
radioligand for clinical PET imaging