[18F]<scp>JNJ</scp>42259152 binding to phosphodiesterase 10A, a key regulator of medium spiny neuron excitability, is altered in the presence of cyclic <scp>AMP</scp>

Abstract

Abstract Phosphodiesterase 10A ( PDE 10A) is a key regulator of medium spiny neuron excitability. Therefore, it plays an important role in the regulation of motor, reward, and cognitive processes. Despite the interest in PDE 10A as a drug and positron emission tomography ( PET ) imaging target, little is known about the regulation of PDE 10A enzymatic activity. This study aimed to further investigate the role of cAMP in the regulation of PDE 10A activity and PDE 10A PET imaging. Using [ 18 F] JNJ 42259152 as radioligand, we investigated alterations in PDE 10A binding secondary to changes in cAMP levels. An in vitro striatum homogenate binding assay was developed to determine K D and B max of [ 18 F] JNJ 42259152. Homogenate binding was assessed after addition of increasing concentrations of exogenous cAMP (1, 10, and 100 μM). Rats were treated using JNJ 49137530 and rolipram to induce in vivo alterations of cAMP . The effect of the induced cAMP alterations on PDE 10A binding was assessed by comparing [ 18 F] JNJ 42259152 micro PET studies after treatment to micro PET studies acquired at baseline conditions prior to treatment. In vitro binding affinity of [ 18 F] JNJ 42259152 was higher in the presence of cAMP compared to baseline conditions ( K D = 3.17 ± 0.91 nM with 10 μM cAMP vs. K D = 6.62 ± 0.7 nM at baseline). Inhibition of PDE 4 using rolipram significantly increased [ 18 F] JNJ 42259152 binding ( BP ND = 2.61 ± 0.50 vs. 1.91 ± 0.36 at baseline). Administration of the PDE 2 inhibitor JNJ 49137530 significantly increased PDE 10A binding potential ( BP ND = 2.74 ± 0.22 vs. 2.05 ± 0.16 at baseline). Our data indicate an important role for cAMP in the regulation of PDE 10A activity. Additionally, our data show a profound interaction between several PDEs in striatum. image