Cross-Species Triage of SERT-Oriented Polyheteroaryl Candidates Prioritizes AD20/UtIA-0108 as an Early Neuroactive...

Depression and stress-related disorders remain important targets for the development of new neuroactive compounds. We evaluated three imidazo[1,2-a]pyridine-[1,2,5]oxadiazolo[3,4-b]pyrazine derivatives, selected by a SERT-oriented computational screen, using chemical characterization, zebrafish embryo toxicity, larval and adult zebrafish behavioural assays, mouse behavioural HPLC, and qPCR experiments. AD19/UtIA-0167 had the highest computational consensus but showed greater embryo toxicity and no consistent advantage in adult zebrafish. AD20/UtIA-0108 showed a distinct larval locomotor profile, increased middle-zone occupancy after chronic exposure in stressed adult zebrafish, and was therefore examined in mice. Chronic AD20 increased latency to enter the dark compartment; whereas, time in the light compartment, open-field measures and forced-swim immobility were unchanged. HPLC and qPCR changes were region-specific and did not demonstrate direct SERT engagement. AD20 should therefore be regarded as an early neuroactive candidate from a SERT-oriented screen, not as a confirmed SERT inhibitor or antidepressant. Interpretation across species is limited by the duplicated zebrafish serotonin-transporter system, waterborne exposure and the limited scope of the mouse behavioural effect. Direct transporter assays, pharmacokinetic studies and independent behavioural replication are required.