Molecular imaging of monocrotaline-induced pulmonary vascular disease with radiolabeled linear adrenomedullin.
No test currently exists for molecular imaging of pulmonary arterial hypertension (PAH). Adrenomedullin is a vasodilator peptide predominantly cleared by pulmonary endothelial receptors. We developed a linear adrenomedullin derivative radiolabeled with (99m)Tc ((99m)Tc-AM-L) for imaging of pulmonary circulation and tested its capacity to detect anomalies of pulmonary circulation caused by PAH.


METHODS
PAH was induced by monocrotaline in rats and compared with controls. After 5 wk, (99m)Tc-AM-L was injected intravenously. Plasma kinetics were measured, lung activity was determined in vivo after 30 min using a nuclear camera, and lung activity was determined ex vivo in explanted lungs. Expression of adrenomedullin receptors was measured in lung homogenates.


RESULTS
The plasma levels of (99m)Tc-AM-L significantly increased in PAH by approximately 2-fold. Uptake by the lungs was homogeneous but greatly reduced in PAH by about 70%. In vivo retention was 14% +/- 1% (mean +/- SD) of the injected dose in controls and 4% +/- 1% in PAH (P < 0.0001). A similar reduction was measured ex vivo (6.0 +/- 1.6 percentage injected dose per gram [%ID/g] vs. 0.95 +/- 0.21 %ID/g, P < 0.0001). The expression of the heterodimeric component of the adrenomedullin receptor, receptor activity modifying protein 2, was also greatly reduced in PAH lungs (P < 0.001). Interestingly, right ventricular uptake of (99m)Tc-AM-L was increased by PAH (P = 0.02) and correlated with the degree of right ventricular hypertrophy (r = 0.83, P = 0.001).


CONCLUSIONS
Pulmonary uptake of (99m)Tc-AM-L is greatly reduced in monocrotaline-induced PAH. This novel molecular imaging agent may be useful in the diagnosis and follow-up of pulmonary vascular disorders.
Dupuis
Jocelyn
J
Research Center, Montreal Heart Institute, University of Montreal, Quebec, Canada. jocelyn.dupuis@bellnet.ca
Harel
François
F
Fu
Yan
Y
Nguyen
Quang Trinh
QT
Letourneau
Myriam
M
Préfontaine
Annick
A
Fournier
Alain
A
D053607:Adrenomedullin / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000378:metabolism*; D007553:Isotope Labeling; D008168:Lung / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D016686:Monocrotaline; D009928:Organ Specificity; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013667:Technetium / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D019275:Radiopharmaceuticals; D053607:Adrenomedullin; D016686:Monocrotaline; D013667:Technetium