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PET imaging of cerebral ischemia with a peripheral benzodiazepine receptor ligand
ABSTRACTS / NeuroImage 31 (2006) T12 – T43
T35
Oral Presentation No.: 022
PET imaging of cerebral ischemia with a peripheral benzodiazepine receptor ligand M. Imaizumi,1 S. Zoghbi,1 J. Hong,1 J. Musachio,1 H.J. Kim,2 D.-M. Chuang,2 V. Pike,1 Robert Innis,1 and M. Fujita1 1
2
Molecular Imaging Branch, NIMH, Bethesda, MD, USA Molecular Neurobiology Section, NIMH, Bethesda, MD, USA
Objectives: Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia. The PBR ligand [C-11]PK11195 has been used to detect in vivo neuroinflammatory changes in a variety of neurological insults but has a high percentage of nonspecific binding. We recently developed a promising PET ligand ([C-11]3-[N-acetyl-N-(2-methoxybenzyl) amino]-4-phenoxypyridine, [C-11]PBR28) with high affinity and excellent ratios of specific to nonspecific binding. Our aim was to quantify PBRs in a rat permanent middle cerebral artery occlusion (pMCAO) model of neuroinflammation. Methods: Brain data were acquired using the ATLAS PET scanner at 4 and 7 days after pMCAO. [C-11]PBR28 was intravenously administered to 4 Sprague – Dawley rats with pMCAO for 2 bolus and 2 bolus plus infusion (B/I) studies. In 2 B/I studies, 10 and 20 mg/kg PK111195 was administered at 60 min after [C-11]PBR28 injection to measure specific binding. Rat’s brains were sampled after PET imaging for in vitro autoradiography using [H-3]PK11195. PET time – activity curves were obtained by drawing regions of interest on the center of the ischemic area (I), peri-ischemic area (P) and contralateral side of ischemia (C). Eleven arterial samples were taken to measure input function using radioHPLC. Total distribution volumes (VT’s) were calculated using an unconstrained 2-tissue compartment (2C) model. Three areas of I, P and C were used to compare results between in vivo [C-11]PBR28 imaging and in vitro [H-3]PK11195 autoradiography. Results: [C-11]PBR28 images showed higher uptake in P than in I with homogeneous distributions in C. Compared to C, I and P showed 100 – 190% and 140 – 290% increases in VT’, respectively. Brain uptake of [C-11]PBR28 was blocked with the receptor saturating doses of non-radiolabeled PK11195 in 2 B/I studies. [H-3]PK11195 autoradiography showed significantly higher activity in P compared with C (P < 0.01). Visual localizations of PBRs were similar between in vivo [C-11]PBR28 imaging and [H-3]PK11195 autoradiography. There was a significant correlation between P/C and I/C ratios obtained from the VT’ by 2C and those from [H-3]PK11195 autoradiography activity (r = 0.90, P < 0.01). Conclusions: [C-11]PBR28 PET is a sensitive method to detect increases in PBRs. Distribution and changes of PBRs can now be studied by measuring VT’ of [C-11]PBR28 in rat ischemic models. doi:10.1016/j.neuroimage.2006.04.025
T35
Oral Presentation No.: 022
PET imaging of cerebral ischemia with a peripheral benzodiazepine receptor ligand M. Imaizumi,1 S. Zoghbi,1 J. Hong,1 J. Musachio,1 H.J. Kim,2 D.-M. Chuang,2 V. Pike,1 Robert Innis,1 and M. Fujita1 1
2
Molecular Imaging Branch, NIMH, Bethesda, MD, USA Molecular Neurobiology Section, NIMH, Bethesda, MD, USA
Objectives: Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia. The PBR ligand [C-11]PK11195 has been used to detect in vivo neuroinflammatory changes in a variety of neurological insults but has a high percentage of nonspecific binding. We recently developed a promising PET ligand ([C-11]3-[N-acetyl-N-(2-methoxybenzyl) amino]-4-phenoxypyridine, [C-11]PBR28) with high affinity and excellent ratios of specific to nonspecific binding. Our aim was to quantify PBRs in a rat permanent middle cerebral artery occlusion (pMCAO) model of neuroinflammation. Methods: Brain data were acquired using the ATLAS PET scanner at 4 and 7 days after pMCAO. [C-11]PBR28 was intravenously administered to 4 Sprague – Dawley rats with pMCAO for 2 bolus and 2 bolus plus infusion (B/I) studies. In 2 B/I studies, 10 and 20 mg/kg PK111195 was administered at 60 min after [C-11]PBR28 injection to measure specific binding. Rat’s brains were sampled after PET imaging for in vitro autoradiography using [H-3]PK11195. PET time – activity curves were obtained by drawing regions of interest on the center of the ischemic area (I), peri-ischemic area (P) and contralateral side of ischemia (C). Eleven arterial samples were taken to measure input function using radioHPLC. Total distribution volumes (VT’s) were calculated using an unconstrained 2-tissue compartment (2C) model. Three areas of I, P and C were used to compare results between in vivo [C-11]PBR28 imaging and in vitro [H-3]PK11195 autoradiography. Results: [C-11]PBR28 images showed higher uptake in P than in I with homogeneous distributions in C. Compared to C, I and P showed 100 – 190% and 140 – 290% increases in VT’, respectively. Brain uptake of [C-11]PBR28 was blocked with the receptor saturating doses of non-radiolabeled PK11195 in 2 B/I studies. [H-3]PK11195 autoradiography showed significantly higher activity in P compared with C (P < 0.01). Visual localizations of PBRs were similar between in vivo [C-11]PBR28 imaging and [H-3]PK11195 autoradiography. There was a significant correlation between P/C and I/C ratios obtained from the VT’ by 2C and those from [H-3]PK11195 autoradiography activity (r = 0.90, P < 0.01). Conclusions: [C-11]PBR28 PET is a sensitive method to detect increases in PBRs. Distribution and changes of PBRs can now be studied by measuring VT’ of [C-11]PBR28 in rat ischemic models. doi:10.1016/j.neuroimage.2006.04.025