1 Neurologisk Klinik, Neurocentret, Rigshospitalet, The Capital Region of Denmark2 Klinik for Klinisk Fysiologi, Nuklearmedicin og PET, Diagnostisk Center, Rigshospitalet, The Capital Region of Denmark3 Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari A. Moro, Via Orabona, 4, 70125 Bari, Italy.
Here we describe the design, synthesis, and pharmacological evaluation of a set of compounds structurally related to the high affinity serotonin 5-HT7 receptor agonist N-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (6, LP-211). Specific structural modifications were performed in order to maintain affinity for the target receptor and to improve the selectivity over 5-HT1A and adrenergic α1 receptors. The synthesized compounds have chemical features that could enable labeling with a positron emitter radioisotope (carbon-11 or fluorine-18) and lipophilicity within the range considered optimal for brain penetration and low non-specific binding. 4-[2-(4-Methoxyphenyl)phenyl]-N-(pyridin-4-ylmethyl)piperazinehexanamide (23a) and N-pyridin-4-ylmethyl-3-[4-[2-(4-methoxyphenyl)phenyl]piperazin-1-yl]ethoxy]propanamide (26a) were radiolabeled on the methoxy group with carbon-11. Positron emission tomography (PET) analysis revealed that [(11)C]-23a and [(11)C]-26a were P-glycoprotein (P-gp) substrates and rapidly metabolized, resulting in poor brain uptake. These features were not predicted by in vitro tests.
Bioorganic and Medicinal Chemistry, 2014, Vol 22, Issue 5, p. 1736-1750