Limits...
Synthesis and evaluation of translocator 18 kDa protein (TSPO) positron emission tomography (PET) radioligands with low binding sensitivity to human single nucleotide polymorphism rs6971.

Zanotti-Fregonara P, Zhang Y, Jenko KJ, Gladding RL, Zoghbi SS, Fujita M, Sbardella G, Castellano S, Taliani S, Martini C, Innis RB, Da Settimo F, Pike VW - ACS Chem Neurosci (2014)

Bottom Line: Each radioligand was readily prepared by (11)C-methylation of an N-desmethyl precursor and was found to give a high proportion of TSPO-specific binding in monkey brain.One of these radioligands, [(11)C]7, the direct 4-azaisostere of 1, presents many radioligand properties that are superior to those reported for [(11)C]1, including higher affinity, lower lipophilicity, and stable quantifiable PET signal.Importantly, 7 was also found to show very low sensitivity to the human SNP rs6971 in vitro.

View Article: PubMed Central - PubMed

Affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892-0001, United States.

ABSTRACT
The imaging of translocator 18 kDa protein (TSPO) in living human brain with radioligands by positron emission tomography (PET) has become an important means for the study of neuroinflammatory conditions occurring in several neuropsychiatric disorders. The widely used prototypical PET radioligand [(11)C](R)-PK 11195 ([(11)C](R)-1; [N-methyl-(11)C](R)-N-sec-butyl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide) gives a low PET signal and is difficult to quantify, whereas later generation radioligands have binding sensitivity to a human single nucleotide polymorphism (SNP) rs6971, which imposes limitations on their utility for comparative quantitative PET studies of normal and diseased subjects. Recently, azaisosteres of 1 have been developed with improved drug-like properties, including enhanced TSPO affinity accompanied by moderated lipophilicity. Here we selected three of these new ligands (7-9) for labeling with carbon-11 and for evaluation in monkey as candidate PET radioligands for imaging brain TSPO. Each radioligand was readily prepared by (11)C-methylation of an N-desmethyl precursor and was found to give a high proportion of TSPO-specific binding in monkey brain. One of these radioligands, [(11)C]7, the direct 4-azaisostere of 1, presents many radioligand properties that are superior to those reported for [(11)C]1, including higher affinity, lower lipophilicity, and stable quantifiable PET signal. Importantly, 7 was also found to show very low sensitivity to the human SNP rs6971 in vitro. Therefore, [(11)C]7 now warrants evaluation in human subjects with PET to assess its utility for imaging TSPO in human brain, irrespective of subject genotype.

Show MeSH

Related in: MedlinePlus

Sagittalsummed PET images of brain after intravenous injectionof the same monkey with [11C]7–9 under baseline conditions. Arrows point to the choroid plexusof the fourth ventricle.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4210126&req=5

fig3: Sagittalsummed PET images of brain after intravenous injectionof the same monkey with [11C]7–9 under baseline conditions. Arrows point to the choroid plexusof the fourth ventricle.

Mentions: The ability of radioligands [11C]7–9 to image brain TSPO was tested withPET in rhesus monkeys, first after radioligand injection at baseline,and second after preblocking TSPO with 1 (5 mg/kg, i.v.)at about 5 min before injection of radioligand. Summed PET imagesof monkey brain acquired after radioligand injection (Figure 3) displayed a high level of radioactivity, especiallyin the choroid plexus of the fourth ventricle. High uptake was alsoseen in striatum and cerebellum, and to a lesser extent in corticalregions. Scans from the corresponding preblock experiments showeda very uniform and low distribution of radioactivity, consistent withthe absence of radioligand specific binding to TSPO (data not shown).


Synthesis and evaluation of translocator 18 kDa protein (TSPO) positron emission tomography (PET) radioligands with low binding sensitivity to human single nucleotide polymorphism rs6971.

Zanotti-Fregonara P, Zhang Y, Jenko KJ, Gladding RL, Zoghbi SS, Fujita M, Sbardella G, Castellano S, Taliani S, Martini C, Innis RB, Da Settimo F, Pike VW - ACS Chem Neurosci (2014)

Sagittalsummed PET images of brain after intravenous injectionof the same monkey with [11C]7–9 under baseline conditions. Arrows point to the choroid plexusof the fourth ventricle.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4210126&req=5

fig3: Sagittalsummed PET images of brain after intravenous injectionof the same monkey with [11C]7–9 under baseline conditions. Arrows point to the choroid plexusof the fourth ventricle.
Mentions: The ability of radioligands [11C]7–9 to image brain TSPO was tested withPET in rhesus monkeys, first after radioligand injection at baseline,and second after preblocking TSPO with 1 (5 mg/kg, i.v.)at about 5 min before injection of radioligand. Summed PET imagesof monkey brain acquired after radioligand injection (Figure 3) displayed a high level of radioactivity, especiallyin the choroid plexus of the fourth ventricle. High uptake was alsoseen in striatum and cerebellum, and to a lesser extent in corticalregions. Scans from the corresponding preblock experiments showeda very uniform and low distribution of radioactivity, consistent withthe absence of radioligand specific binding to TSPO (data not shown).

Bottom Line: Each radioligand was readily prepared by (11)C-methylation of an N-desmethyl precursor and was found to give a high proportion of TSPO-specific binding in monkey brain.One of these radioligands, [(11)C]7, the direct 4-azaisostere of 1, presents many radioligand properties that are superior to those reported for [(11)C]1, including higher affinity, lower lipophilicity, and stable quantifiable PET signal.Importantly, 7 was also found to show very low sensitivity to the human SNP rs6971 in vitro.

View Article: PubMed Central - PubMed

Affiliation: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health , Bethesda, Maryland 20892-0001, United States.

ABSTRACT
The imaging of translocator 18 kDa protein (TSPO) in living human brain with radioligands by positron emission tomography (PET) has become an important means for the study of neuroinflammatory conditions occurring in several neuropsychiatric disorders. The widely used prototypical PET radioligand [(11)C](R)-PK 11195 ([(11)C](R)-1; [N-methyl-(11)C](R)-N-sec-butyl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide) gives a low PET signal and is difficult to quantify, whereas later generation radioligands have binding sensitivity to a human single nucleotide polymorphism (SNP) rs6971, which imposes limitations on their utility for comparative quantitative PET studies of normal and diseased subjects. Recently, azaisosteres of 1 have been developed with improved drug-like properties, including enhanced TSPO affinity accompanied by moderated lipophilicity. Here we selected three of these new ligands (7-9) for labeling with carbon-11 and for evaluation in monkey as candidate PET radioligands for imaging brain TSPO. Each radioligand was readily prepared by (11)C-methylation of an N-desmethyl precursor and was found to give a high proportion of TSPO-specific binding in monkey brain. One of these radioligands, [(11)C]7, the direct 4-azaisostere of 1, presents many radioligand properties that are superior to those reported for [(11)C]1, including higher affinity, lower lipophilicity, and stable quantifiable PET signal. Importantly, 7 was also found to show very low sensitivity to the human SNP rs6971 in vitro. Therefore, [(11)C]7 now warrants evaluation in human subjects with PET to assess its utility for imaging TSPO in human brain, irrespective of subject genotype.

Show MeSH
Related in: MedlinePlus