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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

Regional brain distribution; regional brain distribution of radioactivity after tail-vein injection of [11C]CB184, [11C]CB190, [11C]CB148 and [11C](R)-PK11195 in ddY mice is shown in a–d, respectively. Data are expressed as percentage of the injected dose per gram of tissue (%ID/g, mean and SD of four animals). open circle cerebellum, filled circle thalamus, open triangle cortex, filled triangle olfactory bulb. Data of [11C]CB148 (c) was taken from literature [24]
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Fig3: Regional brain distribution; regional brain distribution of radioactivity after tail-vein injection of [11C]CB184, [11C]CB190, [11C]CB148 and [11C](R)-PK11195 in ddY mice is shown in a–d, respectively. Data are expressed as percentage of the injected dose per gram of tissue (%ID/g, mean and SD of four animals). open circle cerebellum, filled circle thalamus, open triangle cortex, filled triangle olfactory bulb. Data of [11C]CB148 (c) was taken from literature [24]

Mentions: Unlabeled reference standard of CB184 and CB190 and their precursors, CB185 and CB189 were prepared according to previously reported method [25]. Carbon-11 was produced by 14N(p, α)11C nuclear reaction using a CYPRIS HM18 cyclotron (Sumitomo Heavy Industries, Tokyo, Japan). [11C]CO2 thus obtained was converted to [11C]methyl triflate using an automated synthesis system (CUPID C-11-BII, Sumitomo Heavy Industries, Tokyo, Japan). The obtained [11C]methyl triflate was trapped in 0.3 mL acetone solution of containing 1 mg of CB185 or CB189 and 0.4 mg of NaOH (Fig. 3). The mixture was then heated at 80 °C for 3 min allowing the methylation reaction to occur. HPLC fractions containing purified [11C]CB184 or [11C]CB190 were collected into an evaporating vessel (HPLC conditions are summarized in Table 1). After removal of solvent, the residue was re-dissolved in the appropriate solvent and analyzed by reverse-phase HPLC (Table 1). The specific radioactivity of compounds was calculated by comparing the injected radioactivity with the corresponding UV peak area at 250 nm. Radiochemical synthesis of [11C](R)-PK11195 was reported elsewhere [26].Fig. 3


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)

Regional brain distribution; regional brain distribution of radioactivity after tail-vein injection of [11C]CB184, [11C]CB190, [11C]CB148 and [11C](R)-PK11195 in ddY mice is shown in a–d, respectively. Data are expressed as percentage of the injected dose per gram of tissue (%ID/g, mean and SD of four animals). open circle cerebellum, filled circle thalamus, open triangle cortex, filled triangle olfactory bulb. Data of [11C]CB148 (c) was taken from literature [24]
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: Regional brain distribution; regional brain distribution of radioactivity after tail-vein injection of [11C]CB184, [11C]CB190, [11C]CB148 and [11C](R)-PK11195 in ddY mice is shown in a–d, respectively. Data are expressed as percentage of the injected dose per gram of tissue (%ID/g, mean and SD of four animals). open circle cerebellum, filled circle thalamus, open triangle cortex, filled triangle olfactory bulb. Data of [11C]CB148 (c) was taken from literature [24]
Mentions: Unlabeled reference standard of CB184 and CB190 and their precursors, CB185 and CB189 were prepared according to previously reported method [25]. Carbon-11 was produced by 14N(p, α)11C nuclear reaction using a CYPRIS HM18 cyclotron (Sumitomo Heavy Industries, Tokyo, Japan). [11C]CO2 thus obtained was converted to [11C]methyl triflate using an automated synthesis system (CUPID C-11-BII, Sumitomo Heavy Industries, Tokyo, Japan). The obtained [11C]methyl triflate was trapped in 0.3 mL acetone solution of containing 1 mg of CB185 or CB189 and 0.4 mg of NaOH (Fig. 3). The mixture was then heated at 80 °C for 3 min allowing the methylation reaction to occur. HPLC fractions containing purified [11C]CB184 or [11C]CB190 were collected into an evaporating vessel (HPLC conditions are summarized in Table 1). After removal of solvent, the residue was re-dissolved in the appropriate solvent and analyzed by reverse-phase HPLC (Table 1). The specific radioactivity of compounds was calculated by comparing the injected radioactivity with the corresponding UV peak area at 250 nm. Radiochemical synthesis of [11C](R)-PK11195 was reported elsewhere [26].Fig. 3

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