Assessing dynamic metabolic heterogeneity in prostate cancer patients via total-body [ 68 Ga]Ga-PSMA-11 PET/CT imaging: quantitative analysis of [ 68 Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs

Purpose This study aimed to quantitatively assess [ 68 Ga]Ga-PSMA-11 uptake in pathological lesions and normal organs in prostate cancer using the total-body [ 68 Ga]Ga-PSMA-11 PET/CT and to characterize the dynamic metabolic heterogeneity of prostate cancer. Methods Dynamic total-body [ 68 Ga]Ga-PSMA-11 PET/CT scans were performed on ten prostate cancer patients. Manual delineation of volume-of-interests (VOIs) was performed on multiple normal organs displaying high [ 68 Ga]Ga-PSMA-11 uptake, as well as pathological lesions. Time-to-activity curves (TACs) were generated, and the four compartment models including one-tissue compartmental model (1T1k), reversible one-tissue compartmental model (1T2k), irreversible two-tissue compartment model (2T3k) and reversible two-tissue compartmental model (2T4k) were fitted to each tissue TAC. Various rate constants, including K 1 (forward transport rate from plasma to the reversible compartment), k 2 (reverse transport rate from the reversible compartment to plasma), k 3 (tracer binding on the PSMA-receptor and its internalization), k 4 (the externalization rate of the tracer) and K i (net influx rate), were obtained. The selection of the optimal model for describing the uptake of both lesions and normal organs was determined using the Akaike information criteria (AIC). Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off values for differentiating physiological and pathological [ 68 Ga]Ga-PSMA-11 uptake. Results Both 1T1k and 1T2k models showed relatively high AIC values compared to the 2T3k and 2T4k models in both pathological lesions and normal organs. The kinetic behavior of pathological lesions was better described by the 2T3k model compared to the 2T4k model, while the normal organs were better described by the 2T4k model. Significant variations in kinetic metrics, such as K 1 , k 2 , and k 3 , and K i , were observed among normal organs with high [ 68 Ga]Ga-PSMA-11 uptake and pathological lesions. The high K i value in normal organs was primarily determined by elevated K 1 and low k 3 , rather than k 2 . Conversely, the high K i value in pathological lesions, ranking second to the kidney and similar to salivary glands and spleen, was predominantly determined by the highest k 3 value. Notably, k 3 exhibited the highest performance in distinguishing between physiological and pathological [ 68 Ga]Ga-PSMA-11 uptake, with an area under the curve (AUC) of 0.844 (95% CI, 0.773–0.915), sensitivity of 82.9%, and specificity of 74.1%. The k 3 values showed better performance than SUVmean (AUC, 0.659), SUVmax (AUC, 0.637), and other kinetic parameter including K 1 (AUC, 0.604), k 2 (AUC, 0.634), and K i (AUC, 0.651). Conclusions Significant discrepancies in kinetic metrics were detected between pathological lesions and normal organs, despite their shared high uptake of [ 68 Ga]Ga-PSMA-11. Notably, the k 3 value exhibits a noteworthy capability to distinguish between pathological lesions and normal organs with elevated [ 68 Ga]Ga-PSMA-11 uptake. This discovery implies that k 3 holds promise as a prospective imaging biomarker for distinguishing between pathologic and non-specific [ 68 Ga]Ga-PSMA-11 uptake in patients with prostate cancer.