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Radiosynthesis and in vivo evaluation of two imidazopyridineacetamides, [(11)C]CB184 and [ (11)C]CB190, as a PET tracer for 18 kDa translocator protein: direct comparison with [ (11)C](R)-PK11195.

Hatano K, Sekimata K, Yamada T, Abe J, Ito K, Ogawa M, Magata Y, Toyohara J, Ishiwata K, Biggio G, Serra M, Laquintana V, Denora N, Latrofa A, Trapani G, Liso G, Suzuki H, Sawada M, Nomura M, Toyama H - Ann Nucl Med (2015)

Bottom Line: Biodistribution of these compounds was compared with that of [(11)C]CB148 and [(11)C](R)-PK11195.The DVR was 1.15 ± 0.10 for [(11)C](R)-PK11195 and was 1.15 ± 0.09 for [(11)C]CB184.The sensitivity to detect neuroinflammation activity was similar for [(11)C]CB184 and [(11)C](R)-PK11195.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8522, Japan, hatanok@md.tsukuba.ac.jp.

ABSTRACT

Objective: We report synthesis of two carbon-11 labeled imidazopyridines TSPO ligands, [(11)C]CB184 and [(11)C]CB190, for PET imaging of inflammatory process along with neurodegeneration, ischemia or brain tumor. Biodistribution of these compounds was compared with that of [(11)C]CB148 and [(11)C](R)-PK11195.

Methods: Both [(11)C]CB184 and [(11)C]CB190 having (11)C-methoxyl group on an aromatic ring were readily prepared using [(11)C]methyl triflate. Biodistribution and metabolism of the compounds were examined with normal mice. An animal PET study using 6-hydroxydopamine treated rats as a model of neurodegeneration was pursued for proper estimation of feasibility of the radioligands to determine neuroinflammation process.

Results: [(11)C]CB184 and [(11)C]CB190 were obtained via O-methylation of corresponding desmethyl precursor using [(11)C]methyl triflate in radiochemical yield of 73 % (decay-corrected). In vivo validation as a TSPO radioligand was carried out using normal mice and lesioned rats. In mice, [(11)C]CB184 showed more uptake and specific binding than [(11)C]CB190. Metabolism studies showed that 36 % and 25 % of radioactivity in plasma remained unchanged 30 min after intravenous injection of [(11)C]CB184 and [(11)C]CB190, respectively. In the PET study using rats, lesioned side of the brain showed significantly higher uptake than contralateral side after i.v. injection of either [(11)C]CB184 or [(11)C](R)-PK11195. Indirect Logan plot analysis revealed distribution volume ratio (DVR) between the two sides which might indicate lesion-related elevation of TSPO binding. The DVR was 1.15 ± 0.10 for [(11)C](R)-PK11195 and was 1.15 ± 0.09 for [(11)C]CB184.

Conclusion: The sensitivity to detect neuroinflammation activity was similar for [(11)C]CB184 and [(11)C](R)-PK11195.

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Related in: MedlinePlus

Structures of TSPO radioligands
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Fig1: Structures of TSPO radioligands

Mentions: [11C](R)-PK11195 was the first TSPO radioligand applied to CNS diseases involving neuroinflammation process with PET [11]. Many clinical brain imaging studies were reported [reviewed in 8], however, the high degree of nonspecific uptake of [11C](R)-PK11195 complicates the quantification and modeling of the PET data [12–15]. This significantly limits its sensitivity in detecting brain disorders. In this consequence, numerous radioligands for TSPO have been reported (Fig. 1). Zhang first reported carbon-11 labeled phenoxyphenyl acetamide, DAA1106 [16] and its fluoroalkyl congeners [17]. Briard reported structurally related phenoxypyridinyl acetamide, [11C]PBR28 [18] and later Wilson also offered its fluoroalkyl congener, [18F]FEPPA [19]. Another structural category should be referred to as “heterocyclic acetamide”. Kassiou and co-workers reported pyrazolopyrimidinyl acetamides, [11C]DPA-713 [20] and [18F]DPA-714 [21]. Another example was dihydropurinylacetamide, [11C]AC-5216 contributed by Zhang et al. [22]. Mattner offered I-123 labeled imidazopyridineacetamide, [123I]CLINDE, for single photon emission computed tomography imaging [23].Fig. 1


Radiosynthesis and in vivo evaluation of two imidazopyridineacetamides, [(11)C]CB184 and [ (11)C]CB190, as a PET tracer for 18 kDa translocator protein: direct comparison with [ (11)C](R)-PK11195.

Hatano K, Sekimata K, Yamada T, Abe J, Ito K, Ogawa M, Magata Y, Toyohara J, Ishiwata K, Biggio G, Serra M, Laquintana V, Denora N, Latrofa A, Trapani G, Liso G, Suzuki H, Sawada M, Nomura M, Toyama H - Ann Nucl Med (2015)

Structures of TSPO radioligands
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4835529&req=5

Fig1: Structures of TSPO radioligands
Mentions: [11C](R)-PK11195 was the first TSPO radioligand applied to CNS diseases involving neuroinflammation process with PET [11]. Many clinical brain imaging studies were reported [reviewed in 8], however, the high degree of nonspecific uptake of [11C](R)-PK11195 complicates the quantification and modeling of the PET data [12–15]. This significantly limits its sensitivity in detecting brain disorders. In this consequence, numerous radioligands for TSPO have been reported (Fig. 1). Zhang first reported carbon-11 labeled phenoxyphenyl acetamide, DAA1106 [16] and its fluoroalkyl congeners [17]. Briard reported structurally related phenoxypyridinyl acetamide, [11C]PBR28 [18] and later Wilson also offered its fluoroalkyl congener, [18F]FEPPA [19]. Another structural category should be referred to as “heterocyclic acetamide”. Kassiou and co-workers reported pyrazolopyrimidinyl acetamides, [11C]DPA-713 [20] and [18F]DPA-714 [21]. Another example was dihydropurinylacetamide, [11C]AC-5216 contributed by Zhang et al. [22]. Mattner offered I-123 labeled imidazopyridineacetamide, [123I]CLINDE, for single photon emission computed tomography imaging [23].Fig. 1

Bottom Line: Biodistribution of these compounds was compared with that of [(11)C]CB148 and [(11)C](R)-PK11195.The DVR was 1.15 ± 0.10 for [(11)C](R)-PK11195 and was 1.15 ± 0.09 for [(11)C]CB184.The sensitivity to detect neuroinflammation activity was similar for [(11)C]CB184 and [(11)C](R)-PK11195.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8522, Japan, hatanok@md.tsukuba.ac.jp.

ABSTRACT

Objective: We report synthesis of two carbon-11 labeled imidazopyridines TSPO ligands, [(11)C]CB184 and [(11)C]CB190, for PET imaging of inflammatory process along with neurodegeneration, ischemia or brain tumor. Biodistribution of these compounds was compared with that of [(11)C]CB148 and [(11)C](R)-PK11195.

Methods: Both [(11)C]CB184 and [(11)C]CB190 having (11)C-methoxyl group on an aromatic ring were readily prepared using [(11)C]methyl triflate. Biodistribution and metabolism of the compounds were examined with normal mice. An animal PET study using 6-hydroxydopamine treated rats as a model of neurodegeneration was pursued for proper estimation of feasibility of the radioligands to determine neuroinflammation process.

Results: [(11)C]CB184 and [(11)C]CB190 were obtained via O-methylation of corresponding desmethyl precursor using [(11)C]methyl triflate in radiochemical yield of 73 % (decay-corrected). In vivo validation as a TSPO radioligand was carried out using normal mice and lesioned rats. In mice, [(11)C]CB184 showed more uptake and specific binding than [(11)C]CB190. Metabolism studies showed that 36 % and 25 % of radioactivity in plasma remained unchanged 30 min after intravenous injection of [(11)C]CB184 and [(11)C]CB190, respectively. In the PET study using rats, lesioned side of the brain showed significantly higher uptake than contralateral side after i.v. injection of either [(11)C]CB184 or [(11)C](R)-PK11195. Indirect Logan plot analysis revealed distribution volume ratio (DVR) between the two sides which might indicate lesion-related elevation of TSPO binding. The DVR was 1.15 ± 0.10 for [(11)C](R)-PK11195 and was 1.15 ± 0.09 for [(11)C]CB184.

Conclusion: The sensitivity to detect neuroinflammation activity was similar for [(11)C]CB184 and [(11)C](R)-PK11195.

Show MeSH
Related in: MedlinePlus