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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

Logan plot analysis; representative indirect Logan plot analysis [28, 29] of right and left striatal uptake of control (open circle) or 6-OHDA injured (closed circle) rat after intravenous injection of [11C](R)-PK11195 (a) or [11C]CB184 (b) in a rat. The analyses were carried out employing uptake of the lesioned side as target and the contralateral side as reference. After linear regression of the each plot, distribution volume ratio (DVR) between right and left striatum was obtained from its slope (see text)
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Fig5: Logan plot analysis; representative indirect Logan plot analysis [28, 29] of right and left striatal uptake of control (open circle) or 6-OHDA injured (closed circle) rat after intravenous injection of [11C](R)-PK11195 (a) or [11C]CB184 (b) in a rat. The analyses were carried out employing uptake of the lesioned side as target and the contralateral side as reference. After linear regression of the each plot, distribution volume ratio (DVR) between right and left striatum was obtained from its slope (see text)

Mentions: Time-activity curve after intravenous injection of [11C](R)-PK11195 or [11C]CB184 are shown in Fig. 4. Right and left striatum showed similar TACs when radioligands were injected in control animals (Fig. 4a, c). In contrast, 6-OHDA lesion resulted in increased uptake of both radioligands in lesioned side compared to contralateral side (Fig. 4b, d). Visual inspection revealed [11C](R)-PK11195 was cleared more rapidly than [11C]CB184. Although we tried serial two PET scans from one batch of the each tracer, the difference of pharmacological dose between low and high dose groups (Table 5) did not affect striatal uptake of both tracers (data are not shown). TACs thus obtained were analyzed by an indirect Logan plot method as reported by Converse for [11C](R)-PK11195 employing uptake of the lesioned side as target and the contralateral side as Reference [28, 29]. Figure 5 shows satisfactory linear fitting of [11C](R)-PK11195 or [11C]CB184 in both control and lesioned animals. DVRs of [11C](R)-PK11195 in control and lesioned animals were 1.02 ± 0.08 (n = 4) and 1.15 ± 0.10 (n = 5), respectively, (mean ± SD). DVRs for [11C]CB184 in control and lesioned animals were 1.03 ± 0.03 (n = 4) and 1.15 ± 0.09 (n = 6), respectively. Both radioligands showed significantly different DVR values between control and lesioned rats.Fig. 4


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)

Logan plot analysis; representative indirect Logan plot analysis [28, 29] of right and left striatal uptake of control (open circle) or 6-OHDA injured (closed circle) rat after intravenous injection of [11C](R)-PK11195 (a) or [11C]CB184 (b) in a rat. The analyses were carried out employing uptake of the lesioned side as target and the contralateral side as reference. After linear regression of the each plot, distribution volume ratio (DVR) between right and left striatum was obtained from its slope (see text)
© Copyright Policy
Related In: Results  -  Collection

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

Fig5: Logan plot analysis; representative indirect Logan plot analysis [28, 29] of right and left striatal uptake of control (open circle) or 6-OHDA injured (closed circle) rat after intravenous injection of [11C](R)-PK11195 (a) or [11C]CB184 (b) in a rat. The analyses were carried out employing uptake of the lesioned side as target and the contralateral side as reference. After linear regression of the each plot, distribution volume ratio (DVR) between right and left striatum was obtained from its slope (see text)
Mentions: Time-activity curve after intravenous injection of [11C](R)-PK11195 or [11C]CB184 are shown in Fig. 4. Right and left striatum showed similar TACs when radioligands were injected in control animals (Fig. 4a, c). In contrast, 6-OHDA lesion resulted in increased uptake of both radioligands in lesioned side compared to contralateral side (Fig. 4b, d). Visual inspection revealed [11C](R)-PK11195 was cleared more rapidly than [11C]CB184. Although we tried serial two PET scans from one batch of the each tracer, the difference of pharmacological dose between low and high dose groups (Table 5) did not affect striatal uptake of both tracers (data are not shown). TACs thus obtained were analyzed by an indirect Logan plot method as reported by Converse for [11C](R)-PK11195 employing uptake of the lesioned side as target and the contralateral side as Reference [28, 29]. Figure 5 shows satisfactory linear fitting of [11C](R)-PK11195 or [11C]CB184 in both control and lesioned animals. DVRs of [11C](R)-PK11195 in control and lesioned animals were 1.02 ± 0.08 (n = 4) and 1.15 ± 0.10 (n = 5), respectively, (mean ± SD). DVRs for [11C]CB184 in control and lesioned animals were 1.03 ± 0.03 (n = 4) and 1.15 ± 0.09 (n = 6), respectively. Both radioligands showed significantly different DVR values between control and lesioned rats.Fig. 4

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