Synthesis and evaluation of [(11)C]PyrATP-1, a novel radiotracer for PET imaging of glycogen synthase kinase-3β (GSK-3β).
BACKGROUND
The dysfunction of glycogen synthase kinase-3β (GSK-3β) has been implicated in a number of diseases, including Alzheimer's disease. The ability to non-invasively quantify GSK-3β activity in vivo is therefore of critical importance, and this work is focused upon development of inhibitors of GSK-3β radiolabeled with carbon-11 to examine quantification of the enzyme using positron emission tomography (PET) imaging.


METHODS
(11)C PyrATP-1 was prepared from the corresponding desmethyl-piperazine precursor in an automated synthesis module. In vivo rodent and primate imaging studies were conducted on a Concorde MicroPET P4 scanner to evaluate imaging properties and in vitro autoradiography studies with rat brain samples were carried out to examine specific binding.


RESULTS
2035±518MBq (55±14mCi) of [(11)C]PyrATP-1 was obtained (1%-2% non-corrected radiochemical yield at end-of-synthesis based upon [(11)C]CO2) with high chemical (>95%) and radiochemical (>99%) purities, and good specific activities (143±52GBq/μmol (3874±1424Ci/mmol)), n=5. In vivo microPET imaging studies revealed poor brain uptake in rodents and non-human primates. Pretreatment of rodents with cyclosporin A resulted in moderately increased brain uptake suggesting Pgp transporter involvement. Autoradiography demonstrated high levels of specific binding in areas of the rodent brain known to be rich in GSK-3β.


CONCLUSIONS
(11)C PyrATP-1 is readily synthesized using standard carbon-11 radiochemistry. However the poor brain uptake in rodents and non-human primates indicates that the radiotracer is not suitable for the purposes of quantifying GSK-3β in neurological and psychiatric disorders.
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Erin L
EL
Cole
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Xia
X
Shao
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Phillip
P
Sherman
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Carole
C
Quesada
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Maria V
MV
Fawaz
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA.
Timothy J
TJ
Desmond
Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI, USA; The Interdepartmental Program in Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA. Electronic address: pjhscott@umich.edu.
Peter J H
PJ
Scott
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging; D002250:Carbon Radioisotopes; D060326:Chemistry Techniques, Synthetic; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011849:Radioactive Tracers; D011854:Radiochemistry; D051381:Rats; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002250:Carbon Radioisotopes; D047428:Protein Kinase Inhibitors; C000594153:PyrATP-1; D011719:Pyrazines; D011849:Radioactive Tracers; D013449:Sulfonamides; D011718:Pyrazinamide; D038362:Glycogen Synthase Kinase 3
Alzheimer’s disease; Carbon-11; Glycogen synthase kinase; Positron emission tomography