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[(18)F]Nifene is an agonist PET radioligand developed to image α4β2* nicotinic acetylcholine receptors (nAChRs). This work aims to quantify the receptor density (Bmax) of α4β2* nAChRs and the in vivo (apparent) dissociation constant (KDapp) of [(18)F]nifene. Multiple-injection [(18)F]nifene experiments with varying cold nifene masses were conducted on four rhesus monkeys with a microPET P4 scanner. Compartment modeling techniques were used to estimate regional Bmax values and a global value of KDapp. The fast kinetic properties of [(18)F]nifene also permitted alternative estimates of Bmax and KDapp at transient equilibrium with the same experimental data using Scatchard-like methodologies. Averaged across subjects, the compartment modeling analysis yielded Bmax values of 4.8±1.4, 4.3±1.0, 1.2±0.4, and 1.2±0.3 pmol/mL in the regions of antereoventral thalamus, lateral geniculate, frontal cortex, and subiculum, respectively. The KDapp of nifene was 2.4±0.3 pmol/mL. The Scatchard analysis based on graphical evaluation of the data after transient equilibrium yielded Bmax estimations comparable to the modeling results with a positive bias of 28%. These findings show the utility of [(18)F]nifene for measuring α4β2* nAChR Bmax in vivo in the rhesus monkey with a single PET experiment.

[18F]Nifene is an agonist PET radioligand developed to image α4β2* nicotinic acetylcholine receptors (nAChRs). This work aims to quantify the receptor density (Bmax) of α4β2* nAChRs and the in vivo (apparent) dissociation constant (KDapp) of [18F]nifene. Multiple-injection [18F]nifene experiments with varying cold nifene masses were conducted on four rhesus monkeys with a microPET P4 scanner. Compartment modeling techniques were used to estimate regional Bmax values and a global value of KDapp. The fast kinetic properties of [18F]nifene also permitted alternative estimates of Bmax and KDapp at transient equilibrium with the same experimental data using Scatchard-like methodologies. Averaged across subjects, the compartment modeling analysis yielded Bmax values of 4.8±1.4, 4.3±1.0, 1.2±0.4, and 1.2±0.3 pmol/mL in the regions of antereoventral thalamus, lateral geniculate, frontal cortex, and subiculum, respectively. The KDapp of nifene was 2.4±0.3 pmol/mL. The Scatchard analysis based on graphical evaluation of the data after transient equilibrium yielded Bmax estimations comparable to the modeling results with a positive bias of 28%. These findings show the utility of [18F]nifene for measuring α4β2* nAChR Bmax in vivo in the rhesus monkey with a single PET experiment. [ABSTRACT FROM AUTHOR]

Abstract: Serotonin (5-HT) dysfunction has been implicated in neuropsychiatric illnesses and may play a pivotal role in the differential prevalence of depression between the sexes. Previous PET studies have revealed sex-based differences in 5-HT1A binding potential (BPND). The binding potential is a function of the radioligand-receptor affinity (1/KDapp), and receptor density (Bmax). In this work, we use a multiple-injection (MI) PET protocol and the 5-HT1A receptor antagonist, [18F]mefway, to compare sex-based differences of in vivo affinity, Bmax, and BPND in rhesus monkeys. Methods: PET [18F]mefway studies were performed on 17 (6m, 11f) rhesus monkeys using a 3-injection protocol that included partial saturation injections of mefway. Compartmental modeling was performed using a model to account for non-tracer doses of mefway for the estimation of KDapp and Bmax. BPND estimates were also acquired from the first injection (high specific activity [18F]mefway, 90-minute duration) for comparison using the cerebellum (CB) as a reference region. Regions of interest were selected in 5-HT1A binding regions of the hippocampus (Hp), dorsal anterior cingulate cortex (dACC), amygdala (Am), and raphe nuclei (RN). Results: Female subjects displayed significantly (*p<0.05) lower KDapp in the Hp (−32%), Am (−38%), and RN (−37%). Only the Hp displayed significant differences in Bmax with females having a Bmax of −29% compared to males. Male subjects demonstrated significantly lower BPND measurements in the Am (14%) and RN (29%). Conclusion: These results suggest that the higher BPND values found in females are the result of lower [18F]mefway KDapp. Although a more experimentally complex measurement, separate assay of KDapp and Bmax provides a more sensitive measure than BPND to identify the underlying differences between females and males in 5-HT1A function. [Copyright &y& Elsevier]