NK1 occupancy of MK-0869 and L-743,310 in ferret brain using [¹⁸F]SPARQ-D2

Objectives MK-0869 has shown efficacy in the treatment of emesis in a ferret model induced by cisplatin and in humans during chemotherapy (Tattersall et al., 2000), while L-743,310 did not show efficacy in ferrets due to lack of brain penetration (Tattersall et al., 1996). PET studies were performed in ferrets using the NK1 receptor radiotracer [¹⁸F]SPARQ-D2 to determine the relationship between NK1 occupancy and emesis inhibition efficacy.

Methods Ferrets were scanned under baseline conditions (N=5) and following IV administration of MK-0869 or L-743,310 (0.1 - 3 mg/kg, N=2 per dose) given 30 min before tracer injection. [¹⁸F]SPARQ-D2 [37-96 MBq] was given as a bolus and PET data were acquired for 3 hours. PET images were co-registered with an MRI-based ferret brain template. [¹⁸F]SPARQ-D2 binding potential (BP) in the striatum was calculated using the area under the tissue curves (90-150 min post-[¹⁸F]SPARQ-D2 injection) and a population-based cerebellum curve as a reference region.

Results Between animal variability of [¹⁸F]SPARQ-D2 BP at baseline was 12%. NK1 occupancies following 3 mg/kg or 0.3 mg/kg MK-0869 were 96% ± 1% and 93% ± 1% respectively. Administration of 0.1 mg/kg MK-0869, a dose that did not previously show efficacy in emesis inhibition in ferrets, resulted in 83% ± 5% NK1 occupancy. Administration of 3 mg/kg L-743,310 resulted in BP values that were not statistically different from baseline (p=0.50).

Conclusions These results indicate that efficacy in the inhibition of emesis symptoms in ferrets requires central NK1 receptor occupancy >90% and further supports the hypothesis that central NK1 occupancy is required for anti-emetic action