An in vivo comparison of 5-HT_1A receptor density (B_max) and BP_ND using [¹⁸F]mefway

Objectives The nondisplaceable binding potential (BP_ND) represents an index of receptor density (B_max), in vivo ligand-receptor affinity (1/K_D), and nonspecific receptor binding (f_ND). Although often used as a metric for measuring disease specific changes in B_max, several studies using different PET radioligands have shown that there is often no correlation between B_max and BP_ND. The goal of this work was to examine this relation using the 5-HT_1A PET ligand [¹⁸F]mefway (MEF) and carefully designed experiments to measure B_max and in vivo dissociation constant (K_Dapp).

Methods Three-injection experiments, including partial saturation injections of MEF, were designed for high precision measurement of K_Dapp (= k_off/k_on) and B_max in the 5-HT_1A receptor-rich area of the mesial temporal cortex (MTC). PET experiments were conducted in six (2m,4f) anesthetized rhesus monkeys using arterial sampling to generate the input function. The “hot-cold” model was used to derive estimates of B_max and K_Dapp with uncertainties calculated using generated-noise simulations. BP_ND measurements were performed using the Logan DVR (BP_ND=DVR-1) from the first injection data (high specific activity MEF and 90 minute duration) using the cerebellum as a reference region, which has shown to exhibit no measurable specific binding of MEF. BP_ND was regressed with K_Dapp, B_max, and B_max/K_Dapp.

Results The fractional uncertainties in the parameter estimates were: 6% (4-8%) for B_max and 6% (4-11%) for K_Dapp. The intersubject coefficient of variation (CV=sd/mean) was 22%, 27%, and 21% (BP_ND,K_Dapp,B_max). Regression analysis showed no significant correlation between BP_ND and B_max (p=0.26) or K_Dapp (p=0.43). A significant correlation was found between BP_ND and B_max/K_Dapp in the MTC (p=0.018).

Conclusions Our results from six subjects show that for MEF BP_ND is not a proxy of Bmax or K_Dapp, but a combination of the two (B_max/K_Dapp), indicating each index provides a unique measure of ligand-receptor binding.

Research Support AA017706, MH086014, AG030524, AA12277, T32CA0092