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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.


Related in: MedlinePlus

Effect of competing drugs (CLINME, PK11195, Ro 5-4864, and flumazenil, 1 mg/Kg) on [123I]-CLINME uptake in peripheral organs of normal rat. Results are average of 3–6 rats ± SD, 30 min p.i. of [123I]-CLINME. Unit is percent injected dose per gram (%ID/g) (∗∗P < 0.01).
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fig4: Effect of competing drugs (CLINME, PK11195, Ro 5-4864, and flumazenil, 1 mg/Kg) on [123I]-CLINME uptake in peripheral organs of normal rat. Results are average of 3–6 rats ± SD, 30 min p.i. of [123I]-CLINME. Unit is percent injected dose per gram (%ID/g) (∗∗P < 0.01).

Mentions: Drug competition experiments were carried out to test the ability of TSPO and CBR drugs to inhibit [123I]-CLINME uptake in the brain and in peripheral organs (Figures 3 and 4). PK11195 was the most potent in inhibiting the uptake of [123I]-CLINME in the heart, lungs, and kidney by 87, 81, and 72% (P < 0.01), respectively, compared to control animals. A significant decrease (P < 0.05) of 36% was also observed in the olfactory bulbs. A nonsignificant reduction was observed in the adrenals. With this drug, the uptake of [123I]-CLINME in blood was significantly increased by 29% compared to controls (P < 0.01). Ro 5-4864 also significantly reduced the uptake of activity in the heart, kidney, lungs, and the remainder of the brain by 77, 68, 62, and 23% (P < 0.01), respectively. A nonsignificant reduction was observed in the olfactory bulbs. The reduction of uptake of [123I]-CLINME in the blood was not significant, while the concentration in the adrenals was significantly increased by 73% compared to controls (P < 0.01). With flumazenil nonsignificant differences of [123I]-CLINME uptake in peripheral organs and brain were observed.


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)

Effect of competing drugs (CLINME, PK11195, Ro 5-4864, and flumazenil, 1 mg/Kg) on [123I]-CLINME uptake in peripheral organs of normal rat. Results are average of 3–6 rats ± SD, 30 min p.i. of [123I]-CLINME. Unit is percent injected dose per gram (%ID/g) (∗∗P < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig4: Effect of competing drugs (CLINME, PK11195, Ro 5-4864, and flumazenil, 1 mg/Kg) on [123I]-CLINME uptake in peripheral organs of normal rat. Results are average of 3–6 rats ± SD, 30 min p.i. of [123I]-CLINME. Unit is percent injected dose per gram (%ID/g) (∗∗P < 0.01).
Mentions: Drug competition experiments were carried out to test the ability of TSPO and CBR drugs to inhibit [123I]-CLINME uptake in the brain and in peripheral organs (Figures 3 and 4). PK11195 was the most potent in inhibiting the uptake of [123I]-CLINME in the heart, lungs, and kidney by 87, 81, and 72% (P < 0.01), respectively, compared to control animals. A significant decrease (P < 0.05) of 36% was also observed in the olfactory bulbs. A nonsignificant reduction was observed in the adrenals. With this drug, the uptake of [123I]-CLINME in blood was significantly increased by 29% compared to controls (P < 0.01). Ro 5-4864 also significantly reduced the uptake of activity in the heart, kidney, lungs, and the remainder of the brain by 77, 68, 62, and 23% (P < 0.01), respectively. A nonsignificant reduction was observed in the olfactory bulbs. The reduction of uptake of [123I]-CLINME in the blood was not significant, while the concentration in the adrenals was significantly increased by 73% compared to controls (P < 0.01). With flumazenil nonsignificant differences of [123I]-CLINME uptake in peripheral organs and brain were observed.

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.


Related in: MedlinePlus