[Triumf-seminars] TRIUMF Colloquium today at 14:00

[TRIUMF Seminars]

Date/Time: Thu 2017-04-06 at 14:00

Location:  Auditorium          

Speaker:   Hal Selnick (Merck)

Title:     P-gp Matters

Abstract: Calcitonin Gene-Related Peptide Receptor (CGRP-R) antagonists including olcegepant and telcagepant have demonstrated efficacy in the acute treatment of migraine comparable to the "gold standard" triptans in clinical trials. In addition to being a potent vasodilator, CGRP is hypothesized to be a = key signaling neurotransmitter which is thought to interact with centrally located CGRP receptors to mediate pain transmission during the migraine headache. To address the question of the effective site of action of CGRP–R antagonists in migraine, several different methods to estimate receptor engagement in both the periphery and the CNS were explored including Positron Emission Tomography (PET). The medicinal chemistry strategy included exploration of both 11C and 18F PET tracers and led to the discovery of [11C]MK-4232, a PET tracer suitable for the quantitative determination of central CGRP-R occupancy levels in primates and with appropriate properties for transfer to the clinical setting.  Using PET to address CNS activity, important features of CNS penetration of CGRP antagonists have been elucidated.  The relative contributions of binding affinity, free unbound fraction in plasma, CSF levels of drug, measured free concentration in brain tissue and P-gp transport of CGRP-R antagonists to central receptor occupancy will be discussed



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