Positron emission tomography of [18F]‐big endothelin‐1 reveals renal excretion but tissue‐specific conversion to [18F]‐endothelin‐1 in lung and liver

Abstract

Big endothelin-1 (ET-1) circulates in plasma but does not bind to ET receptors until converted to ET-1 by smooth muscle converting enzymes. We hypothesized that tissue-specific conversion of [(18)F]-big ET-1 to [(18)F]-ET-1 could be imaged dynamically in vivo within target organs as binding to ET receptors. [(18)F]-big ET-1 conversion imaged in vivo following infusion into rats using positron emission tomography (PET). [(18)F]-big ET-1 was rapidly cleared from the circulation (t(1/2)= 2.9 +/- 0.1 min). Whole body microPET images showed highest uptake of radioactivity in three major organs. In lungs and liver, time activity curves peaked within 2.5 min, then plateaued reaching equilibrium after 10 min, with no further decrease after 120 min. Phosphoramidon did not alter half life of [(18)F]-big ET-1 but uptake was reduced in lung (42%) and liver (45%) after 120 min, consistent with inhibition of enzyme conversion and reduction of ET-1 receptor binding. The ET(A) antagonist, FR139317 did not alter half-life of [(18)F]-big ET-1 (t(1/2)= 2.5 min) but radioactivity was reduced in all tissues except for kidney consistent with reduction in binding to ET(A) receptors. In kidney, however, the peak in radioactivity was higher but time to maximum accumulation was slower ( approximately 30 min), which was increased by phosphoramidon, reflecting renal excretion with low conversion and binding to ET receptors. A major site for conversion was within the vasculature of the lung and liver, whereas uptake in kidney was more complex, reflecting excretion of [(18)F]-big ET-1 without conversion to ET-1.