We present the most recent advances in photo-detector design employed in time of flight positron emission tomography (ToF-PET). PET is a molecular imaging modality that collects pairs of coincident (temporally correlated) annihilation photons emitted from the patient body. The annihilation photon detector typically comprises a scintillation crystal coupled to a fast photo-detector. ToF information provides better localization of the annihilation event along the line formed by each detector pair, resulting in an overall improvement in signal to noise ratio (SNR) of the reconstructed image. Apart from the demand for high luminosity and fast decay time of the scintillation crystal, proper design and selection of the photo-detector and methods for arrival time pick-off are a prerequisite for achieving excellent time resolution required for ToF-PET. We review the two types of photo-detectors used in ToF-PET: photomultiplier tubes (PMTs) and silicon photo-multipliers (SiPMs) with a special focus on SiPMs.

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This study investigates the physical limitations involved in the extraction of accurate timing information from pixellated scintillation detectors for positron emission tomography (PET). Accurate physical modeling of the scintillation detection process, from scintillation light generation through detection, is devised and performed for varying detector attributes, such as the crystal element length, light yield, decay time and surface treatment. The dependence of light output and time resolution on these attributes, as well as on the photon interaction depth (DoI) of the annihilation quanta within the crystal volume, is studied and compared with experimental results. A theoretical background which highlights the importance of different time blurring factors for instantaneous ('ideal') and exponential ('realistic') scintillation decay is developed and compared with simulated data. For the case of a realistic scintillator, our experimental and simulation findings suggest that dependence of detector performance on DoI is more evident for crystal elements with rough ('as cut') compared to polished surfaces (maximum observed difference of 64% (25%) and 22% (19%) in simulation (measurement) for light output and time resolution, respectively). Furthermore we observe distinct trends of the detector performance dependence on detector element length and surface treatment. For short crystals (3 × 3 × 5 mm(3)) an improvement in light output and time resolution for 'as cut' compared to polished crystals is observed (3% (7%) and 9% (9%) for simulation (measurement), respectively). The trend is reversed for longer crystals (3 × 3 × 20 mm(3)) and an improvement in light output and time uncertainty for polished compared to 'as cut' crystals is observed (36% (6%) and 40% (20%) for simulation (measurement), respectively). The results of this study are used to guide the design of PET detectors with combined time of flight (ToF) and DoI features.

Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.