11C-AC-5216: a novel PET ligand for peripheral benzodiazepine receptors in the primate brain.
Developing a PET ligand for imaging of the peripheral benzodiazepine receptor (PBR; Translocator Protein [18 kDa] TSPO) is of great importance for studying its role in glial cells in the injured brain and in neurodegenerative disorders, such as Alzheimer's disease. The aim of this study was to synthesize and evaluate N-benzyl-N-ethyl-2-(7-(11)C-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ((11)C-AC-5216) as a PET ligand for imaging PBR in the primate brain.


METHODS
AC-5216 and its desmethyl precursor (compound 1) were synthesized starting from commercially available compounds. The radiosynthesis of (11)C-AC-5216 was performed through the reaction of compound 1 with (11)C-CH(3)I in the presence of NaH. The in vivo brain regional distribution was determined in mice (dissection) and a monkey (PET).


RESULTS
(11)C-AC-5216 (800-1,230 MBq; n = 25) was obtained with a radiochemical purity of 98% and a specific activity of 85-130 GBq/mumol at the end of synthesis. After injection of (11)C-AC-5216 into mice, a high accumulation of radioactivity was found in the lungs, heart, adrenal glands, and other PBR-rich organs. In the mouse brain, high radioactivity was observed in the olfactory bulb and cerebellum. Radioactivity in these regions was inhibited by nonradioactive AC-5216 or PK11195 but was not decreased by central benzodiazepine receptor-selective flumazenil and Ro15-4513. A PET study of the monkey brain determined that (11)C-AC-5216 had a relatively high uptake in the occipital cortex, a rich PBR-dense area in the primate brain. Pretreatment with nonradioactive AC-5216 and PK11195 reduced the radioactivity of (11)C-AC-5216 in the occipital cortex significantly, suggesting its high specific binding with PBR in the brain. Metabolite analysis demonstrated that (11)C-AC-5216 was stable in vivo in the mouse brain, although it was metabolized in the plasma of mice and the monkey.


CONCLUSIONS
(11)C-AC-5216 is a promising PET ligand for imaging PBR in rodent and primate brains.
Zhang
Ming-Rong
MR
Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan. zhang@nirs.go.jp
Kumata
Katsushi
K
Maeda
Jun
J
Yanamoto
Kazuhiko
K
Hatori
Akiko
A
Okada
Maki
M
Higuchi
Makoto
M
Obayashi
Shigeru
S
Suhara
Tetsuya
T
Suzuki
Kazutoshi
K
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D008253:Macaca mulatta; D051379:Mice; D049268:Positron-Emission Tomography; D011687:Purines / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011963:Receptors, GABA-A / Q000378:metabolism*; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D011687:Purines; D019275:Radiopharmaceuticals; D011963:Receptors, GABA-A