In this work, we propose and test a new approach for nonlinear kinetic parameters’ estimation from dynamic PET data. A technique is discussed, to derive an analytical closed-form expression of the compartmental model used for kinetic parameters’ evaluation, using an auxiliary parameter set, with the aim of reducing the computational burden and speeding up the fitting of these complex mathematical expressions to noisy TACs. Two alternative algorithms based on numeric calculations are considered and compared to the new proposal. We perform a simulation study aimed at (i) assessing agreement between the proposed method and other conventional ways of implementing compartmental model fitting, and (ii) quantifying the reduction in computational time required for convergence. It results in a speed-up factor of ~120 when compared to a fully numeric version, or ∼38, with respect to a more conventional implementation, while converging to very similar values for the estimated model parameters. The proposed method is also tested on dynamic 3D PET clinical data of four control subjects. The results obtained supported those of the simulation study, and provided input and promising perspectives for the application of the proposed technique in clinical practice.