To evaluate the utility of labeled L-amino acids (AA) for imaging regional myocardial AA metabolism by positron computed tomography (PCT), the myocardial uptake and clearance of Ala,* Glu, Gln, Asp, Leu tagged with N-13, and of C-11-tagged Asp, and oxaloacetate (Oxal), were examined in 44 experiments at control, during ischemia, and after transaminase inhibition. The myocardial time-activity curves recorded after intracoronary tracer injection had two clearance phases (an early and a late) for all N-13 AA, and three (early, intermediate, late) for the two C-11 compounds, with significantly different clearance half-times of 18.7 +/- 8.0 (s.d.) sec for the early phase, 141.7 +/- 56.5 sec for the intermediate, and 61.2 +/- 43.5 min for the late phase. The residual fractions ranged from 0.07 to 0.23 in normal myocardium, and consistently increased with ischemia by 0.01-0.07 for N-13-labeled Ala, Glu, Asp, and Leu, but not for N-13 Gln and C-11 compounds. Transaminase inhibition shortened the half-times of the late phases of N-13-labeled Ala, Glu, Asp, and Leu; had no effect on t1/2 of N-13 Gln and C-11 Oxal; and resulted in a loss of C-11 CO2 production and of the intermediate phase for C-11 Asp. On the PCT images, N-13 activity from labeled Ala and Glu was not decreased in an ischemic segment despite a significant flow reduction, as demonstrated by N-13 NH3 imaging and labeled microspheres. From the results, a three-compartment tracer kinetic model is proposed for the noninvasive quantification of Krebscycle activity, protein synthesis, and metabolic derangements related to ischemia.