18F]JNJ42259152 binding to phosphodiesterase 10A, a key regulator of medium spiny neuron excitability, is altered in the presence of cyclic AMP.

Abstract

Phosphodiesterase 10A (PDE10A) 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 PDE10A as a drug and positron emission tomography (PET) imaging target, little is known about the regulation of PDE10A enzymatic activity. This study aimed to further investigate the role of cAMP in the regulation of PDE10A activity and PDE10A PET imaging. Using [18 F]JNJ42259152 as radioligand, we investigated alterations in PDE10A binding secondary to changes in cAMP levels. An invitro striatum homogenate binding assay was developed to determine KD and Bmax of [18 F]JNJ42259152. Homogenate binding was assessed after addition of increasing concentrations of exogenous cAMP (1, 10, and 100μM). Rats were treated using JNJ49137530 and rolipram to induce invivo alterations of cAMP. The effect of the induced cAMP alterations on PDE10A binding was assessed by comparing [18 F]JNJ42259152 microPET studies after treatment to microPET studies acquired at baseline conditions prior to treatment. In vitro binding affinity of [18 F]JNJ42259152 was higher in the presence of cAMP compared to baseline conditions (KD =3.17±0.91 nM with 10μM cAMP vs. KD =6.62±0.7 nM at baseline). Inhibition of PDE4 using rolipram significantly increased [18 F]JNJ42259152 binding (BPND =2.61±0.50 vs. 1.91±0.36 at baseline). Administration of the PDE2 inhibitor JNJ49137530 significantly increased PDE10A binding potential (BPND =2.74±0.22 vs. 2.05±0.16 at baseline). Our data indicate an important role for cAMP in the regulation of PDE10A activity. Additionally, our data show a profound interaction between several PDEs in striatum.