Use of an [18F]setoperone bolus + infusion protocol to delineate age related reduction in 5HT2A receptor binding potential in female rhesus monkeys

Abstract

The physiologic process of aging is known to have an effect on the brain concentration of some monoaminergic receptors. In addition, studies have suggested a causal link between sex hormones and these receptor changes. Accordingly, we were interested to see in our colony of geriatric rhesus monkeys if we could demonstrate an age- and sex-related difference in 5HT2A receptor concentration in the brain using the PET tracer [18F] Setoperone. This tracer has a 10-50x greater affinity for the 5-HT2A receptor than the D2 receptor, but provides a specific signal for both receptors in vivo. Since D2 receptor density is low in cortical regions and 5HT2A is high, while the opposite is true in striatum, [18F] Setoperone can be used to evaluate both receptors. Chase studies with risperidone, a non-selective antagonist of both 5-HT2A and D2 demonstrated significant displacement of the tracer from both 5-HT2A and D2 receptors. Studies were conducted in propofol anesthetized, older (n=5, 26–29 yrs) female Rhesus monkeys and young female (n=2, 8 yrs) and male Rhesus monkeys (n=2, 8 and 10 yrs) as controls in an ECAT HR+ PET camera. At the time of the scans, estradiol levels were 95 11 pg/ml in the young female monkeys compared to 35.3 6.5 pg/ml in the older monkeys. [18F] Setoperone was administered as a bolus followed by a matched constant-rate infusion for 200 minutes, adjusted to compensate for tracer elimination in the bolus, to achieve steady-state brain uptake. Tracer uptake reached a steady state in the brain after 120 min (reflected by constant target-to-cerebellum ratio). Indices of 5HT2A and D2 receptor binding were calculated from the occipital cortex/cerebellum and striatum/cerebellum ratios between 140 and 200 minutes, respectively. The cerebellum was used as a reference region since it is essentially devoid of both 5-HT2A and D2 receptors. The uptake ratios of occipital cortex/cerebellum binding (an index of the 5-HT2A receptor binding potential) and striatum/cerebellum (an index of the D2 receptor binding potential) were calculated. The test-retest reproducibility of this protocol was found to be < 10% in male Rhesus monkeys. Results indicated an 15% and 24% reduction in binding potential for D2 and 5HT2A receptors respectively in the older females compared to the young females. As expected, the binding potential for 5HT2A receptor in young males was comparable to that in the young females. These studies suggest [18F] Setoperone may be used in a convenient protocol to show age related reductions in 5HT2A and D2 receptor binding in post-menopausal woman. An advantage of using such a protocol with [18F] setoperone is that both 5-HT2A and D2 receptors can be evaluated in the same study.