2-{4-[-Pyridin-4-yl-1-(2-[18F]fluoro-ethyl)-1 H-pyrazol-3-yl]-phenoxymethyl}-quinoline

Excerpt

Phosphodiesterases (PDEs) are composed of at least 11 families of enzymes that hydrolyze cyclic 3´,5´-adenosine monophosphate (cAMP) and/or cyclic 3´,5´-guanosine monophosphate (cGMP) to the corresponding inactive 5´-AMP and 5´-GMP, respectively (1, 2). These second-messenger cyclic nucleotides are formed in response to stimuli (such as hormones, neurotransmitters, and cytokines) to regulate cellular functions. PDEs are essential in the termination of cellular responses via their degradation of cyclic nucleotides. PDE type-10A (PDE10A) is a dual-specificity PDE that can act on both cAMP and cGMP (3). PDE10A is found mainly in the brain (striatum) and testes, with low concentrations in other tissues (4). PDE10A may play a role in the regulation of glutamatergic and dopaminergic functions in neurons (5, 6). PDE10A inhibitors have been studied in the treatment of neuropsychiatric disorders such as schizophrenia, Huntington’s disease, Parkinson’s disease, obsessive-compulsive disorder, and addiction (7-11).

1-(3,4-Dimethoxybenzyl)-6,7-dimethoxyisoquinoline (papaverine) has been found to be a specific inhibitor of PDE10A with 50% inhibition concentration (IC₅₀) values of 36 nM for PDE10A, 1,300 nM for PDE3A, and 320 nM for PDE4D (9). 1-(3-[¹¹C]Methoxy-4-methoxybenzyl)-6,7-dimethoxyisoquinoline ([¹¹C]Papaverine)has been evaluated as a positron emission tomography (12) agent for the non-invasive study of PDE10A in the brain in rats and monkeys (13). However, the results of these studies indicated that the rapid brain clearance of the tracer limits its utility as a PET agent for in vivo measurements of PDE10A. In this chapter, 2-{4-[-pyridin-4-yl-1-(2-[¹⁸F]fluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline ([¹⁸F]JNJ4151047) was found to be a selective inhibitor of PED10A (>1,000-fold better selectivity than the other nine PDE subtypes) with an IC₅₀ value of 0.5 nM for PDE10A (14). [¹⁸F]JNJ4151047 has been evaluated in rats and PED10A-knockout mice for in vivo brain imaging of PED10A activity.