Synthesis and evaluation of [(11)C]PyrATP-1, a novel radiotracer for PET imaging of glycogen synthase kinase-3β (GSK-3β).

Abstract

INTRODUCTION:

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.

CONCLUSION:

(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.

• Authors: Erin L Cole, Xia Shao, Phillip Sherman, Carole Quesada, Maria V Fawaz, Timothy J Desmond, Peter J H Scott
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 41 Issue 6 Pg. 507-12 (Jul 2014) ISSN: 1872-9614 [Electronic] United States
• PMID: 24768148 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Carbon Radioisotopes
• Protein Kinase Inhibitors
• PyrATP-1
• Pyrazines
• Radioactive Tracers
• Sulfonamides
• Pyrazinamide
• Glycogen Synthase Kinase 3

Topics

• Animals
• Brain (diagnostic imaging)
• Carbon Radioisotopes
• Chemistry Techniques, Synthetic
• Female
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Positron-Emission Tomography (methods)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Pyrazinamide (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Pyrazines (chemical synthesis, chemistry, pharmacology)
• Radioactive Tracers
• Radiochemistry
• Rats
• Sulfonamides (chemical synthesis, chemistry, pharmacology)