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Background: Dynamic positron emission tomography (dPET) is a nuclear medicine imaging technique providing functional images for organs of interest with applications in oncology, cardiology, and drug discovery. This technique requires the acquisition of the time-course arterial plasma activity concentration, called the arterial input function (AIF), which is conventionally acquired via arterial blood sampling. Purpose: The aim of this study was to (A) optimize the geometry for a novel and cost efficient non-invasive detector called NID designed to measure the AIF for dPET scans through Monte Carlo simulations and (B) develop a clinical data analysis chain to successfully separate the arterial component of a simulated AIF signal from the venous component. Methods:The NID was optimized by using an in-house Geant4-based software package. The sensitive volume of the NID consists of a band of 10 cm long and 1 mm in diameter scintillating fibers placed over a wrist phantom. The phantom was simulated as a cylinder, 10 cm long and 6.413 cm in diameter comprised of polyethylene with two holes placed through it to simulate the patient's radial artery and vein. This phantom design was chosen to match the wrist phantom used in our previous proof of concept work.Two geometries were simulated with different arrangements of scintillating fibers. The first design used a single layer of 64 fibers. The second used two layers, an inner layer with 29 fibers and an outer layer with 30 fibers. Four positron emitting radioisotopes were simulated: 18 F, 11 C, 15 O, and 68 Ga with 100 million simulated decay events per run. The total and intrinsic efficiencies of both designs were calculated as well as the full width half maximum (FWHM) of the signal. In addition, contribution by the annihilation photons versus positrons to the signal was investigated. The results obtained from the two simulated detector models were compared. A clinical data analysis chain using an expectation maximization maximum likelihood algorithm was tested. This analysis chain will be used to separate arterial counts from the total signal. Results: The second NID design with two layers of scintillating fibers had a higher efficiency for all simulations with a maximum increase of 17% total efficiency for 11 C simulation. All simulations had a significant annihilation photon contribution. The signal for 18 F and 11 C was almost entirely due to photons. The clinical data analysis chain was within 1% of the true value for 434 out of 440 trials. Further experimental studies to validate these simulations will be required. Conclusions:The design of the NID was optimized and its efficiency increased through Monte Carlo simulations. A clinical data analysis chain was successfullyThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.