Limits...
Radiosynthesis, In Vivo Biological Evaluation, and Imaging of Brain Lesions with [123I]-CLINME, a New SPECT Tracer for the Translocator Protein.

Mattner F, Quinlivan M, Greguric I, Pham T, Liu X, Jackson T, Berghofer P, Fookes CJ, Dikic B, Gregoire MC, Dolle F, Katsifis A - Dis. Markers (2015)

Bottom Line: The striatum lesion was confirmed and correlated with TSPO expression in astrocytes and activated microglia by immunohistochemistry and autoradiography.Moreover, TSPO changes observed by SPECT imaging were confirmed by immunofluorescence, immunochemistry, and autoradiography.These results indicated that [(123)I]-CLINME is a promising candidate for the quantification and visualization of TPSO expression in activated astroglia using SPECT.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Division, Australian Nuclear Science and Technology Organisation, New Illawarra Road, Lucas Heights, NSW 2234, Australia ; Department of Molecular Imaging, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.

ABSTRACT
The high affinity translocator protein (TSPO) ligand 6-chloro-2-(4'-iodophenyl)-3-(N,N-methylethyl)imidazo[1,2-a]pyridine-3-acetamide (CLINME) was radiolabelled with iodine-123 and assessed for its sensitivity for the TSPO in rodents. Moreover neuroinflammatory changes on a unilateral excitotoxic lesion rat model were detected using SPECT imaging. [(123)I]-CLINME was prepared in 70-80% radiochemical yield. The uptake of [(123)I]-CLINME was evaluated in rats by biodistribution, competition, and metabolite studies. The unilateral excitotoxic lesion was performed by injection of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid unilaterally into the striatum. The striatum lesion was confirmed and correlated with TSPO expression in astrocytes and activated microglia by immunohistochemistry and autoradiography. In vivo studies with [(123)I]-CLINME indicated a biodistribution pattern consistent with TPSO distribution and the competition studies with PK11195 and Ro 5-4864 showed that [(123)I]-CLINME is selective for this site. The metabolite study showed that the extractable radioactivity was unchanged [(123)I]-CLINME in organs which expresses TSPO. SPECT/CT imaging on the unilateral excitotoxic lesion indicated that the mean ratio uptake in striatum (lesion:nonlesion) was 2.2. Moreover, TSPO changes observed by SPECT imaging were confirmed by immunofluorescence, immunochemistry, and autoradiography. These results indicated that [(123)I]-CLINME is a promising candidate for the quantification and visualization of TPSO expression in activated astroglia using SPECT.

No MeSH data available.


Structure of CLINME.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4496498&req=5

fig1: Structure of CLINME.

Mentions: The acetamide structure of CLINME provides a unique opportunity to prepare structurally diverse compounds suitable for the incorporation of a variety of PET and SPECT isotopes. Consequently, N′,N′-methylethyl-6-chloro-(4′-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide or CLINME (Figure 1) has been prepared for radiolabelling with both carbon-11 and iodine-123 for PET and SPECT studies, respectively. We have shown that [11C]-CLINME [29, 30] has demonstrated lower nonspecific binding than [11C]-PK11195 and was better able to depict microglia activation following unilateral excitotoxic lesions in rodent models of inflammation than [11C]-PK11195 [31]. As this molecule also incorporates iodine, it presents an excellent opportunity to also exploit additional studies when radiolabelled with iodine-125 for pharmacological studies as well as with iodine-123 and iodine-124 for use in SPECT and PET imaging, respectively. Here, we report the radiolabelling, in vitro, in vivo pharmacological evaluation of the iodine-123 labelled analogue [123I]-CLINME and its in vivo imaging in a model of the unilateral excitotoxic lesion using SPECT.


Radiosynthesis, In Vivo Biological Evaluation, and Imaging of Brain Lesions with [123I]-CLINME, a New SPECT Tracer for the Translocator Protein.

Mattner F, Quinlivan M, Greguric I, Pham T, Liu X, Jackson T, Berghofer P, Fookes CJ, Dikic B, Gregoire MC, Dolle F, Katsifis A - Dis. Markers (2015)

Structure of CLINME.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4496498&req=5

fig1: Structure of CLINME.
Mentions: The acetamide structure of CLINME provides a unique opportunity to prepare structurally diverse compounds suitable for the incorporation of a variety of PET and SPECT isotopes. Consequently, N′,N′-methylethyl-6-chloro-(4′-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide or CLINME (Figure 1) has been prepared for radiolabelling with both carbon-11 and iodine-123 for PET and SPECT studies, respectively. We have shown that [11C]-CLINME [29, 30] has demonstrated lower nonspecific binding than [11C]-PK11195 and was better able to depict microglia activation following unilateral excitotoxic lesions in rodent models of inflammation than [11C]-PK11195 [31]. As this molecule also incorporates iodine, it presents an excellent opportunity to also exploit additional studies when radiolabelled with iodine-125 for pharmacological studies as well as with iodine-123 and iodine-124 for use in SPECT and PET imaging, respectively. Here, we report the radiolabelling, in vitro, in vivo pharmacological evaluation of the iodine-123 labelled analogue [123I]-CLINME and its in vivo imaging in a model of the unilateral excitotoxic lesion using SPECT.

Bottom Line: The striatum lesion was confirmed and correlated with TSPO expression in astrocytes and activated microglia by immunohistochemistry and autoradiography.Moreover, TSPO changes observed by SPECT imaging were confirmed by immunofluorescence, immunochemistry, and autoradiography.These results indicated that [(123)I]-CLINME is a promising candidate for the quantification and visualization of TPSO expression in activated astroglia using SPECT.

View Article: PubMed Central - PubMed

Affiliation: Life Sciences Division, Australian Nuclear Science and Technology Organisation, New Illawarra Road, Lucas Heights, NSW 2234, Australia ; Department of Molecular Imaging, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia.

ABSTRACT
The high affinity translocator protein (TSPO) ligand 6-chloro-2-(4'-iodophenyl)-3-(N,N-methylethyl)imidazo[1,2-a]pyridine-3-acetamide (CLINME) was radiolabelled with iodine-123 and assessed for its sensitivity for the TSPO in rodents. Moreover neuroinflammatory changes on a unilateral excitotoxic lesion rat model were detected using SPECT imaging. [(123)I]-CLINME was prepared in 70-80% radiochemical yield. The uptake of [(123)I]-CLINME was evaluated in rats by biodistribution, competition, and metabolite studies. The unilateral excitotoxic lesion was performed by injection of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid unilaterally into the striatum. The striatum lesion was confirmed and correlated with TSPO expression in astrocytes and activated microglia by immunohistochemistry and autoradiography. In vivo studies with [(123)I]-CLINME indicated a biodistribution pattern consistent with TPSO distribution and the competition studies with PK11195 and Ro 5-4864 showed that [(123)I]-CLINME is selective for this site. The metabolite study showed that the extractable radioactivity was unchanged [(123)I]-CLINME in organs which expresses TSPO. SPECT/CT imaging on the unilateral excitotoxic lesion indicated that the mean ratio uptake in striatum (lesion:nonlesion) was 2.2. Moreover, TSPO changes observed by SPECT imaging were confirmed by immunofluorescence, immunochemistry, and autoradiography. These results indicated that [(123)I]-CLINME is a promising candidate for the quantification and visualization of TPSO expression in activated astroglia using SPECT.

No MeSH data available.