Abstract: To explore possible mechanisms that might explain the high uptake of peptidic heterodimer ⁶⁸Ga/¹⁷⁷Lu-FAP-RGD in kidneys, we constructed U87MG glioma xenograft models and evaluate the impact of L-lysine on biodistribution of ⁶⁸Ga/¹⁷⁷Lu-FAP-RGD by small animal PET/CT or biodistribution studies. ⁶⁸Ga/¹⁷⁷Lu-FAP-RGD demonstrated high radiochemical labeling yield and radiochemical purity, with good stability in saline. The results of PET/CT imaging showed that pre-injection of 20 mg lysine could significantly inhibit the uptake of ⁶⁸Ga-FAP-RGD in mouse kidneys, in contrast to the control group ((9.77±0.94) vs. (6.78±0.77) %ID/g , P<0.05), whereas both groups exhibited similar tumor uptake ((5.64±0.60) vs. (6.78±0.77) %ID/g , P=0.38). The biodistribution results indicated that compared with the control group, ¹⁷⁷Lu-FAP-RGD radioactivity was significantly reduced in mouse kidneys of the lysine injection group ((11.15±1.33) vs. (6.44±1.42) %ID/g, P<0.01), while other tissues or organs including the tumor ((6.27±1.04) vs. (6.00±0.63) %ID/g, P=0.65) showed insignificant changes. Thus, L-lysine is expected to improve the detection sensitivity of renal lesions by reducing the accumulation of ⁶⁸Ga-FAP-RGD in the kidneys and serve as a potent agent for renal protection against ¹⁷⁷Lu-FAP-RGD induced nephrotoxicity in radionuclide therapy.