TY - JOUR T1 - Preclinical Evaluation of <sup>18</sup>F-JNJ41510417 as a Radioligand for PET Imaging of Phosphodiesterase-10A in the Brain JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1584 LP - 1591 DO - 10.2967/jnumed.110.077040 VL - 51 IS - 10 AU - Sofie Celen AU - Michel Koole AU - Meri De Angelis AU - Ivan Sannen AU - Satish K. Chitneni AU - Jesus Alcazar AU - Stefanie Dedeurwaerdere AU - Dieder Moechars AU - Mark Schmidt AU - Alfons Verbruggen AU - Xavier Langlois AU - Koen Van Laere AU - José Ignacio Andrés AU - Guy Bormans Y1 - 2010/10/01 UR - http://jnm.snmjournals.org/content/51/10/1584.abstract N2 - Phosphodiesterases are enzymes that inactivate the intracellular second messengers 3′,5′-cyclic adenosine-monophosphate and/or cyclic guanosine-monophosphate. Of all 11 known phosphodiesterase families, phosphodiesterase-10A (PDE10A) has the most restricted distribution, with high expression in the striatum. PDE10A inhibitors are pursued as drugs for treatment of neuropsychiatric disorders. We have synthesized and evaluated 18F-JNJ41510417 as a selective and high-affinity radioligand for in vivo brain imaging of PDE10A using PET. Methods: The biodistribution of 18F-JNJ41510417 was evaluated in rats. Rat plasma and perfused brain homogenates were analyzed by high-performance liquid chromatography to quantify radiometabolites. Dynamic small-animal PET was performed in rats and in wild-type and PDE10A knock-out mice and compared with ex vivo autoradiography. Blocking and displacement experiments were performed using the nonradioactive analog and other selective PDE10A inhibitors. Results: Tissue distribution studies showed predominant hepatobiliary excretion, sufficient brain uptake (0.56 ± 0.00 percentage injected dose at 2 min after tracer injection), and continuous accumulation of the tracer in the striatum over time; rapid washout of nonspecific binding from other brain regions was observed. Polar radiometabolites were detected in plasma and brain tissue. Dynamic small-animal PET showed continuous tracer accumulation in the striatum, with rapid decline in the cortex and cerebellum. Pretreatment and chase experiments with PDE10A inhibitors showed that the tracer binding to PDE10A was specific and reversible. Imaging in PDE10A knock-out and wild-type mice further confirmed that binding in the striatum was specific for PDE10A. Conclusion: Experiments in rats and PDE10A knock-out mice indicate that 18F-JNJ41510417 binds specifically and reversibly to PDE10A in the striatum, suggesting that this new fluorinated quinoline derivative is a promising candidate for in vivo imaging of PDE10A using PET. ER -