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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

Correlation between Logan DVR and right to left ratio of histochemical measures; correlation between Logan DVR and right to left ratio of number of tyrosine hydroxylase (TH) positive cell (a, d), of mRNA expression of tumor necrosis factor α (TNFA) (b, e) or interleukin-1β (IL1Β) (c, f) after intravenous injection of [11C](R)-PK11195 (a–c) or [11C]CB184 (d–f) was examined. Both data from control and 6-OHDA reated rats were plotted. mRNA expression level (TNFα and IL-1β) was normalized by expression of NADPH. Data were analyzed for their correlation with Fisher’s transformation. (n = 9 and 10 for [11C]CB184 and [11C](R)-PK11195, respectively). Regression coefficient (R2) and critical value (p) are shown
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Fig6: Correlation between Logan DVR and right to left ratio of histochemical measures; correlation between Logan DVR and right to left ratio of number of tyrosine hydroxylase (TH) positive cell (a, d), of mRNA expression of tumor necrosis factor α (TNFA) (b, e) or interleukin-1β (IL1Β) (c, f) after intravenous injection of [11C](R)-PK11195 (a–c) or [11C]CB184 (d–f) was examined. Both data from control and 6-OHDA reated rats were plotted. mRNA expression level (TNFα and IL-1β) was normalized by expression of NADPH. Data were analyzed for their correlation with Fisher’s transformation. (n = 9 and 10 for [11C]CB184 and [11C](R)-PK11195, respectively). Regression coefficient (R2) and critical value (p) are shown

Mentions: Correlations between the DVR values for [11C](R)-PK11195 or [11C]CB184 and histochemical data were examined. Data for both control and 6-OHDA treated rats are plotted in Fig. 6. Significant correlation (p < 0.05) was only seen between [11C](R)-PK11195 and TH (Fig. 6a). Correlation between [11C]CB184 and TH (Fig. 6d, p = 0.06) was not statistically significant, however, this would be expected with increasing number of data. The tendencies of positive correlation between DVR of [11C](R)-PK11195 or [11C]CB184 and expression of TNFα or IL-1β expression were also observed in spite they lack statistical significance (Fig. 6b, c, e, f).Fig. 6


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)

Correlation between Logan DVR and right to left ratio of histochemical measures; correlation between Logan DVR and right to left ratio of number of tyrosine hydroxylase (TH) positive cell (a, d), of mRNA expression of tumor necrosis factor α (TNFA) (b, e) or interleukin-1β (IL1Β) (c, f) after intravenous injection of [11C](R)-PK11195 (a–c) or [11C]CB184 (d–f) was examined. Both data from control and 6-OHDA reated rats were plotted. mRNA expression level (TNFα and IL-1β) was normalized by expression of NADPH. Data were analyzed for their correlation with Fisher’s transformation. (n = 9 and 10 for [11C]CB184 and [11C](R)-PK11195, respectively). Regression coefficient (R2) and critical value (p) are shown
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4835529&req=5

Fig6: Correlation between Logan DVR and right to left ratio of histochemical measures; correlation between Logan DVR and right to left ratio of number of tyrosine hydroxylase (TH) positive cell (a, d), of mRNA expression of tumor necrosis factor α (TNFA) (b, e) or interleukin-1β (IL1Β) (c, f) after intravenous injection of [11C](R)-PK11195 (a–c) or [11C]CB184 (d–f) was examined. Both data from control and 6-OHDA reated rats were plotted. mRNA expression level (TNFα and IL-1β) was normalized by expression of NADPH. Data were analyzed for their correlation with Fisher’s transformation. (n = 9 and 10 for [11C]CB184 and [11C](R)-PK11195, respectively). Regression coefficient (R2) and critical value (p) are shown
Mentions: Correlations between the DVR values for [11C](R)-PK11195 or [11C]CB184 and histochemical data were examined. Data for both control and 6-OHDA treated rats are plotted in Fig. 6. Significant correlation (p < 0.05) was only seen between [11C](R)-PK11195 and TH (Fig. 6a). Correlation between [11C]CB184 and TH (Fig. 6d, p = 0.06) was not statistically significant, however, this would be expected with increasing number of data. The tendencies of positive correlation between DVR of [11C](R)-PK11195 or [11C]CB184 and expression of TNFα or IL-1β expression were also observed in spite they lack statistical significance (Fig. 6b, c, e, f).Fig. 6

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