First D1-like receptor PET imaging of the rat and primate kidney: implications for human disease monitoring

Abstract

The intrarenal dopamine system is important for signaling and natriuresis, and significant dysfunction is associated with hypertension and kidney disease in ex vivo studies. Dopamine receptors also modulate and are modulated by the renin-angiotensin-aldosterone system. Here, we show the first in vivo measurement of D1-like receptors in the renal cortex of Sprague-Dawley rat and Papio anubis baboon using [(11)C]NNC 112, a positron emission tomography radioligand for D1-like receptors. In addition, we show a D1-like binding potential response to angiotensin II blockade in rats using losartan. Demonstration of self-saturable binding in the rat as well as specific and saturable binding in Papio anubis validate the use of [(11)C]NNC 112 in the first in vivo measurement of renal dopamine D1-like receptors. Furthermore, [(11)C]NNC 112 is a radioligand tool already validated for use in probing human central nervous system (CNS) D1-like receptors. Our work demonstrates specific and saturable non-CNS binding in higher animals and the ability to quantify physiological response to drug treatment and provides a clear path to extend use of [(11)C]NNC 112 to study renal dopamine in humans.

Keywords: dopamine; hypertension; positron emission tomography; renal PET; renal dopamine.

Fig. 1.

Time activity curve of [¹¹C]NNC 112 in rat. Pretreatment with unlabeled NNC 112 reduces binding (77%).

Fig. 2.

A: simultaneous magnetic resonance-positron emission tomography with [¹¹C]NNC 112 in Papio anubis showing high renal cortex uptake at early time points. B: time activity curve of [¹¹C]NNC 112 in drug naive and SCH-23390-pretreated animal. C: volume of distribution of [¹¹C]NNC 112 baseline and pretreated with SCH-23390. D: time activity curves for other peripheral organs in Papio anubis. E: peripheral organ time activity curves in SCH-23390-pretreated animal showing no evidence of specific D₁-like binding, increased biliary excretion.

Fig. 3.

Standardized uptake value of [¹¹C]NNC 112 in drug naive (n = 2) or losartan-pretreated rats showing short-term potentiation of D₁-like binding. Binding of [¹¹C]NNC 112 is increased by 31% at 30 min (P = 0.025, n = 4), but is not significantly different than baseline at 1 h postinjection (P = 0.878, n = 3).