An in silico study on the effect of the radionuclide half-life on PET/CT imaging with PSMA-targeting radioligands.

AIM: The aim of this work was to systematically investigate the influence of the radionuclide half-life and affinity of prostate-specific membrane antigen (PSMA)-targeting ligands on the activity concentration for PET/CT imaging. METHODS: A whole-body physiologically-based pharmacokinetic (PBPK) model with individually estimated parameters of 13 patients with metastatic castration-resistant prostate cancer (mCRPC) was used to simulate the pharmacokinetics of PSMA-targeting radioligands. The simulations were performed with 68Ga (T1/2 = 1.13 h), 18F (T1/2 = 1.83 h), 64Cu (T1/2 = 12.7 h) and for different affinities (dissociation constants KD of 1-0.01 nM) and a commonly used ligand amount of 3 nmol. The activity concentrations were calculated at 1, 2, 3, 4, 8, 12, and 16 h after injection. RESULTS: The highest tumor uptake was achieved 1 h p. i. for 68Ga-PSMA. For 18F-PSMA, the highest tumor uptake was at 1 h p. i. and 2 h p.i for dissociation constants KD  = 1 nM and KD  = 0.1-0.01 nM, respectively. For 64Cu-PSMA, the highest tumor uptake was at 4 h p. i. for dissociation constant KD  = 1 nM and at 4 h p. i. (9 patients) and 8 h p. i. (4 patients) for higher affinities. Compared to 68Ga-PSMA (1 h p. i.), the activity concentrations in the tumor for 18F-PSMA (2 h p. i.) increased maximum 1.3-fold with minor differences for all affinities. For 64Cu-PSMA (4 h p. i.), the improvements were in the range of 2.8 to 3.2-fold for all affinities. CONCLUSIONS: The simulations indicate that the highest tumor-to-background ratio can be achieved after 4 hours in PET/CT using high-affinity 64Cu-PSMA.

Sensitivity Analysis of a Physiologically Based Pharmacokinetic Model Used for Treatment Planning in Peptide Receptor Radionuclide Therapy.

The aim of this work was to evaluate the sensitivity of time-integrated activity coefficients (TIACs) on the erroneously chosen prior knowledge in a physiologically based pharmacokinetic (PBPK) model used for treatment planning in peptide receptor radionuclide therapy (PRRT). Parameters of the PBPK model were fitted to the biokinetic data of 15 patients after the injection of (111)In-DTPAOC. The fittings were performed using fixed parameter values taken from literature as prior knowledge (reference case, Ref). The fixed parameters were gender, physical information (e.g., body weight), dissociation rate koff, dissociation constant KD, fraction of blood flow, and spleen and liver volumes. The fittings were repeated with changed fixed parameters (Changed). The relative deviations (RDs) of TIACs calculated from Changed and Ref were analyzed for kidneys, tumor, liver, spleen, remainder, whole body, and serum. A changed koff has the largest effect on RD, the largest RD values were found for changed koff = 0.001 L/min: RDkidneys = (3 ± 3)%, RDtumor = (0.5 ± 4)%, RDliver = (6 ± 9)%, RDspleen = (5 ± 5)%, RDremainder = (2 ± 31)%, RDserum = (-4 ± 25)%, and RDwholebody = (3 ± 16)%. For other changed parameters, the maximum RDs were <1%. The calculation of organ TIACs in PRRT using the PBPK model was little affected by assigning wrong prior knowledge to the evaluated patients. The calculation of bone marrow-absorbed doses could be affected by the inaccurate TIACs of serum and remainder in the case of an inadequate koff.