Radiosyntheses and in vivo evaluation of carbon-11 PET tracers for PDE10A in the brain of rodent and nonhuman primate.
The radiosyntheses and in vivo evaluation of four carbon-11 labeled quinoline group-containing radioligands are reported here. Radiolabeling of [(11)C]1-4 was achieved by alkylation of their corresponding desmethyl precursors with [(11)C]CH3I. Preliminary biodistribution evaluation in Sprague-Dawley rats demonstrated that [(11)C]1 and [(11)C]2 had high striatal accumulation (at peak time) for [(11)C]1 and [(11)C]2 were 6.0-fold and 4.5-fold at 60 min, respectively. Following MP-10 pretreatment, striatal uptake in rats of [(11)C]1 and [(11)C]2 was reduced, suggesting that the tracers bind specifically to PDE10A. MicroPET studies of [(11)C]1 and [(11)C]2 in nonhuman primates (NHP) also showed good tracer retention in the striatum with rapid clearance from non-target brain regions. Striatal uptake (SUV) of [(11)C]1 reached 1.8 at 30 min with a 3.5-fold striatum:cerebellum ratio. In addition, HPLC analysis of solvent extracts from NHP plasma samples suggested that [(11)C]1 had a very favorable metabolic stability. Our preclinical investigations suggest that [(11)C]1 is a promising candidate for quantification of PDE10A in vivo using PET.
Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
Jinda
J
Fan
Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
Xiang
X
Zhang
Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
Junfeng
J
Li
Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
Hongjun
H
Jin
Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
Prashanth K
PK
Padakanti
Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
Lynne A
LA
Jones
Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
Hubert P
HP
Flores
Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
Yi
Y
Su
Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA.
Joel S
JS
Perlmutter
Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd., St. Louis, MO 63110, USA. Electronic address: tuz@mir.wustl.edu.
Zhude
Z
Tu
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry; D008252:Macaca fascicularis; D008297:Male; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D010727:Phosphoric Diester Hydrolases
CNS; Carbon-11; MP-10; PDE10A; PET imaging