An Empirical Quantitative Structure-Activity Relationship Equation Assists the Discovery of High-Affinity Phosphodiesterase 4D Inhibitors as Leads to PET Radioligands

A positron emission tomography (PET) radioligand for
imaging phosphodiesterase
4D (PDE4D) would benefit drug discovery and the investigation of neuropsychiatric
disorders. The most promising radioligand to date, namely, [11C]T1650, has shown unstable quantification in humans. Structural
elaboration of [11C]T1650 was therefore deemed necessary.
High target affinity in the low nM range is usually required for successful
PET radioligands. In our PDE4D PET radioligand development, we formulated
and optimized an empirical equation (log[IC50 (nM)] = P1
+ P2 + P3 + P4) that well described the relationship between binding
affinity and empirically derived values (P1–P4) for the individual
fragments in four subregions commonly composing each inhibitor (R2 = 0.988, n = 62). This equation
was used to predict compounds that would have high inhibitory potency.
Fourteen new compounds were obtained with IC50 of 0.3–10
nM. Finally, eight compounds were judged to be worthy of future radiolabeling
and evaluation as PDE4D PET radioligands.