11 research outputs found
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
The development of
cannabinoid receptor type 2 (CB2R)
radioligands for positron emission tomography (PET) imaging was intensively
explored. To overcome the low metabolic stability and simultaneously
increase the binding affinity of known CB2R radioligands,
a carborane moiety was used as a bioisostere. Here we report the synthesis
and characterization of carborane-based 1,8-naphthyridinones and thiazoles
as novel CB2R ligands. All tested compounds showed low
nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide
(LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake
in spleen and low uptake in brain. Thus, the introduction of a carborane
moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity
CB2R ligands, while the in vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
The development of
cannabinoid receptor type 2 (CB2R)
radioligands for positron emission tomography (PET) imaging was intensively
explored. To overcome the low metabolic stability and simultaneously
increase the binding affinity of known CB2R radioligands,
a carborane moiety was used as a bioisostere. Here we report the synthesis
and characterization of carborane-based 1,8-naphthyridinones and thiazoles
as novel CB2R ligands. All tested compounds showed low
nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide
(LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake
in spleen and low uptake in brain. Thus, the introduction of a carborane
moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity
CB2R ligands, while the in vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
The development of
cannabinoid receptor type 2 (CB2R)
radioligands for positron emission tomography (PET) imaging was intensively
explored. To overcome the low metabolic stability and simultaneously
increase the binding affinity of known CB2R radioligands,
a carborane moiety was used as a bioisostere. Here we report the synthesis
and characterization of carborane-based 1,8-naphthyridinones and thiazoles
as novel CB2R ligands. All tested compounds showed low
nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide
(LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake
in spleen and low uptake in brain. Thus, the introduction of a carborane
moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity
CB2R ligands, while the in vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
The development of
cannabinoid receptor type 2 (CB2R)
radioligands for positron emission tomography (PET) imaging was intensively
explored. To overcome the low metabolic stability and simultaneously
increase the binding affinity of known CB2R radioligands,
a carborane moiety was used as a bioisostere. Here we report the synthesis
and characterization of carborane-based 1,8-naphthyridinones and thiazoles
as novel CB2R ligands. All tested compounds showed low
nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide
(LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake
in spleen and low uptake in brain. Thus, the introduction of a carborane
moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity
CB2R ligands, while the in vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
The development of
cannabinoid receptor type 2 (CB2R)
radioligands for positron emission tomography (PET) imaging was intensively
explored. To overcome the low metabolic stability and simultaneously
increase the binding affinity of known CB2R radioligands,
a carborane moiety was used as a bioisostere. Here we report the synthesis
and characterization of carborane-based 1,8-naphthyridinones and thiazoles
as novel CB2R ligands. All tested compounds showed low
nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide
(LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake
in spleen and low uptake in brain. Thus, the introduction of a carborane
moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity
CB2R ligands, while the in vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
The development of
cannabinoid receptor type 2 (CB2R)
radioligands for positron emission tomography (PET) imaging was intensively
explored. To overcome the low metabolic stability and simultaneously
increase the binding affinity of known CB2R radioligands,
a carborane moiety was used as a bioisostere. Here we report the synthesis
and characterization of carborane-based 1,8-naphthyridinones and thiazoles
as novel CB2R ligands. All tested compounds showed low
nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide
(LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake
in spleen and low uptake in brain. Thus, the introduction of a carborane
moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity
CB2R ligands, while the in vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
The development of
cannabinoid receptor type 2 (CB2R)
radioligands for positron emission tomography (PET) imaging was intensively
explored. To overcome the low metabolic stability and simultaneously
increase the binding affinity of known CB2R radioligands,
a carborane moiety was used as a bioisostere. Here we report the synthesis
and characterization of carborane-based 1,8-naphthyridinones and thiazoles
as novel CB2R ligands. All tested compounds showed low
nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide
(LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake
in spleen and low uptake in brain. Thus, the introduction of a carborane
moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity
CB2R ligands, while the in vivo pharmacology
still needs to be addressed
Development of the High-Affinity Carborane-Based Cannabinoid Receptor Type 2 PET Ligand [<sup>18</sup>F]LUZ5‑<i>d</i><sub>8</sub>
The development of
cannabinoid receptor type 2 (CB2R)
radioligands for positron emission tomography (PET) imaging was intensively
explored. To overcome the low metabolic stability and simultaneously
increase the binding affinity of known CB2R radioligands,
a carborane moiety was used as a bioisostere. Here we report the synthesis
and characterization of carborane-based 1,8-naphthyridinones and thiazoles
as novel CB2R ligands. All tested compounds showed low
nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide
(LUZ5) exhibiting the highest affinity (0.8 nM). Compound [18F]LUZ5-d8 was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [18F]LUZ5-d8 compared to that of [18F]JHU94620. PET experiments in rats revealed high uptake
in spleen and low uptake in brain. Thus, the introduction of a carborane
moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity
CB2R ligands, while the in vivo pharmacology
still needs to be addressed
<i>N</i><sup>ε</sup>‑Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure–Activity Relationships, and Pharmacokinetic Profiling
Transglutaminase
2 (TGase 2)-catalyzed transamidation represents
an important post-translational mechanism for protein modification
with implications in physiological and pathophysiological conditions,
including fibrotic and neoplastic processes. Consequently, this enzyme
is considered a promising target for the diagnosis of and therapy
for these diseases. In this study, we report on the synthesis and
kinetic characterization of <i>N</i><sup>ε</sup>-acryloyllysine
piperazides as irreversible inhibitors of TGase 2. Systematic structural
modifications on 54 new compounds were performed with a major focus
on fluorine-bearing substituents due to the potential of such compounds
to serve as radiotracer candidates for positron emission tomography.
The determined inhibitory activities ranged from 100 to 10 000
M<sup>–1</sup> s<sup>–1</sup>, which resulted in comprehensive
structure–activity relationships. Structure–activity
correlations using various substituent parameters accompanied by covalent
docking studies provide an advanced understanding of the molecular
recognition for this inhibitor class within the active site of TGase
2. Selectivity profiling of selected compounds for other transglutaminases
demonstrated an excellent selectivity toward transglutaminase 2. Furthermore,
an initial pharmacokinetic profiling of selected inhibitors was performed,
including the assessment of potential membrane permeability and liver
microsomal stability
<i>N</i><sup>ε</sup>‑Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure–Activity Relationships, and Pharmacokinetic Profiling
Transglutaminase
2 (TGase 2)-catalyzed transamidation represents
an important post-translational mechanism for protein modification
with implications in physiological and pathophysiological conditions,
including fibrotic and neoplastic processes. Consequently, this enzyme
is considered a promising target for the diagnosis of and therapy
for these diseases. In this study, we report on the synthesis and
kinetic characterization of <i>N</i><sup>ε</sup>-acryloyllysine
piperazides as irreversible inhibitors of TGase 2. Systematic structural
modifications on 54 new compounds were performed with a major focus
on fluorine-bearing substituents due to the potential of such compounds
to serve as radiotracer candidates for positron emission tomography.
The determined inhibitory activities ranged from 100 to 10 000
M<sup>–1</sup> s<sup>–1</sup>, which resulted in comprehensive
structure–activity relationships. Structure–activity
correlations using various substituent parameters accompanied by covalent
docking studies provide an advanced understanding of the molecular
recognition for this inhibitor class within the active site of TGase
2. Selectivity profiling of selected compounds for other transglutaminases
demonstrated an excellent selectivity toward transglutaminase 2. Furthermore,
an initial pharmacokinetic profiling of selected inhibitors was performed,
including the assessment of potential membrane permeability and liver
microsomal stability