TASP0434299

TASP0434299 (Compound 10) is a radiolabeled ligand for the vasopressin V1b receptor. It exhibits high binding affinity to human and rat V1b receptors, with IC50 values of 0.526 nM and 0.641 nM, respectively, and acts as a potent antagonist for the human V1b receptor, with an IC50 of 0.639 nM. TASP0434299 is a substrate for human and rhesus monkey P-glycoprotein, leading to reduced brain uptake in rhesus monkeys. It binds specifically and saturably to V1b receptors in rat and monkey pituitary tissues both in vitro and in vivo. When radiolabeled with tritium or 11C, TASP0434299 can be used as a prototype V1b receptor radioligand for visualizing V1b receptors in the pituitary of anesthetized monkeys via positron emission tomography.

TASP0434299 efficiently inhibits [³H]AVP binding to membranes of 293FT cells expressing human V₁B receptors, with an IC₅₀ of 0.526 nM, and to rat anterior pituitary membranes expressing endogenous rat V₁B receptors, with an IC₅₀ of 0.641 nM. It also effectively antagonizes AVP-induced [Ca²⁺]ᵢ elevation in CHO-K1 cells expressing human V₁B receptors, with an IC₅₀ of 0.639 nM. TASP0434299, identified as a substrate of human P-glycoprotein, shows an efflux rate of 27.9 at 1 μM concentration in LLC-GA5-COL300 cells. When co-incubated at 1 μM with [³H]TASP0434299 for 120 minutes, it completely blocks specific binding to native rat V₁B receptors in rat anterior pituitary slices and to native rhesus monkey V₁B receptors in monkey anterior pituitary slices. It binds strongly and selectively to human V₁B receptors, with an IC₅₀ of 0.526 nM, showing no detectable affinity for human V₁A, V₂, or oxytocin receptors, and effectively antagonizes V₁B receptor-mediated intracellular calcium mobilization with an IC₅₀ of 0.639 nM.

[3 H]TASP0434299 (0.93 nmol/kg; intravenous injection; single dose) exhibits specific and saturable binding to the V1B receptors in the anterior pituitary of rats. Similarly, 11 C-TASP0434299 (6.1 μg; intravenous injection; single dose) specifically binds to the endogenous vasopressin V1B receptors in the pituitary of rhesus monkeys.