RT Journal Article
SR Electronic
T1 PET radioligand [11C]MePPEP binds with high specific signal to cannabinoid CB1 receptors in nonhuman primate brain
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 60P
OP 60P
VO 48
IS supplement 2
A1 Fumihiko Yasuno
A1 Amira Brown
A1 Sami Zoghbi
A1 Joseph Krushinski
A1 Eyassu Chernet
A1 Johannes Tauscher
A1 John Schaus
A1 Lee Phebus
A1 Amy Chesterfield
A1 Christian Felder
A1 Robert Gladding
A1 Jinsoo Hong
A1 Christer Halldin
A1 Victor Pike
A1 Robert Innis
YR 2007
UL http://jnm.snmjournals.org/content/48/supplement_2/60P.3.abstract
AB 201 Objectives: The cannabinoid CB1 receptor is one of the most abundant in brain and is the target of therapeutic drug development. [11C]MePPEP is a new PET radioligand, which has high CB1 affinity but also moderately high lipophilicity. We assessed the utility of [11C]MePPEP to image CB1 receptors in monkey brain. Methods: We used six male rhesus monkeys for these studies. PET scans of 120 min were acquired in all studies. Receptor pre-blocking studies were performed in two monkeys using rimonabant (3.0 mg/kg,i.v.) and ISPB (1.0 mg/kg,i.v.), both of which are selective for CB1 and have mixed inverse agonist and antagonist properties. A displacement study was also done for one monkey, in which nonradioactive ISPB (1.5 mg/kg i.v.) was injected 60 min after [11C]MePPEP. We compared the uptake of [11C]MePPEP in three studies with and without the administration of 8 mg/kg i.v P-gp inhibitor DCPQ. Results: Brain activity reached high levels of almost 600% SUV within 10-20 min. The regional uptake was consistent with the distribution of CB1 receptors, with highest radioactivity in cerebellum and striatum and lowest in thalamus and pons. Preblockade or displacement with two CB1 selective agents showed that the majority (> 85%) of brain uptake was specific and reversibly bound to CB1 receptors. Regional brain uptake could be quantified as distribution volume relative to the concentration of parent radiotracer in plasma. Approximately 90 min of scanning provided relatively stable measurements of distribution volume. The P-gp inhibitor DCPQ did not significantly increase brain uptake of [11C]MePPEP, suggesting it is not a substrate for this efflux transporter at the blood-brain barrier. Conclusions: [11C]MePPEP is a radioligand with high brain uptake, high specific signal to CB1 receptors, and adequately fast washout from brain that allows quantification with 11C. These promising results in monkey justify studying this radioligand in human subjects.