Single doses of a highly selective inhibitor of phosphodiesterase 1 (lenrispodun) in healthy volunteers: a randomized pharmaco-fMRI clinical trial

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 47; no. 10; pp. 1844 - 1853
• Main Authors: Khalsa, Sahib S., Victor, Teresa A., Kuplicki, Rayus, Yeh, Hung-Wen, Vanover, Kimberly E., Paulus, Martin P., Davis, Robert E.
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.09.2022; Springer International Publishing
• Subjects: Animal cognition; Attention deficit hyperactivity disorder; Blindness; Brain mapping; Brain research; Clinical trials; Dopamine; Dopamine receptors; Drug dosages; Extinction behavior; Fear conditioning; Frontal gyrus; Functional magnetic resonance imaging; Heart failure; Intracellular signalling; Medical imaging; Memory; Neuroimaging; Phosphodiesterase; Placebos
• ISSN: 0893-133X; 1740-634X; 1740-634X
• DOI: 10.1038/s41386-022-01331-3

Lenrispodun is a potent and highly selective inhibitor of phosphodiesterase (PDE) type 1, which is thought to prolong intracellular second messenger signaling within cortical and subcortical dopaminergic brain regions. This is the first study of a PDE1 inhibitor in healthy volunteers using behavioral and neuroimaging approaches to examine its effects on neural targets and to provide a safety and tolerability assessment. The primary objectives were to determine whether lenrispodun induces changes in BOLD fMRI signals in the inferior frontal gyrus (IFG) during the stop signal task, and the dorsal anterior insula (dAI) during the extinction phase of a fear conditioning/extinction task. Using a double-blind, placebo-controlled, within-subjects design, 26 healthy individuals (22 completed all fMRI sessions) received in random order a single oral dose of placebo, lenrispodun 1.0 milligram (mg) or lenrispodun 10.0 mg and completed several tasks in the scanner including the stop signal (n = 24) and fear conditioning/extinction tasks (n = 22). Prespecified region-of-interest analyses for the IFG and dAI were computed using linear mixed models. Lenrispodun induced increases in IFG activity during the stop signal task at 1.0 mg (Cohen's d = 0.63) but not 10.0 mg (Cohen's d = 0.07) vs. placebo. Lenrispodun did not induce changes in dAI activity during fear extinction at either dose. Exploratory outcomes revealed changes in cardiac interoception. Lenrispodun administration was well-tolerated. These results provide evidence that 1.0 mg lenrispodun selectively improved neural inhibitory control without altering fear extinction processing. Future investigations should determine whether lenrispodun improves inhibitory control in target populations such as individuals with attention deficit hyperactivity disorder. Trial registration: ClinicalTrials.gov identifier: NCT03489772.