PET detector technologies for next-generation molecular imaging: From single-positron counting to single-photoelectron counting

Positron Emission Tomography (PET) is one of the most relevant medical imaging techniques utilized for cancer detection and tumor staging. The success of PET relies on the high sensitivity and accuracy to detect and quantify molecular probe concentrations, in the order of picomole/liter. Although there are several positron-emitting molecular probes available, the 18F-fludeoxyglucose (18F-FDG) contributes remarkably to the high PET specificity and sensitivity. Since the success of PET imaging is strongly connected to the 18F-FDG, this imaging technique is also known as FDG-PET. In FDG-PET imaging three elements are key: - the molecular probe, - a PET scanner, - and an image reconstruction algorithm. The molecular probe is the contrast enhancement agent, which is administrated to the patient and absorbed by the target volumes. The emitted radiation produced by electron-positron annihilation is detected by the PET scanner, and the detection information is utilized to reconstruct a volumetric probe distribution. In essence, a PET scanner is a large acquisition system composed of thousands of channels that detect coincident gamma-photons generated during electron-positron annihilations. Typically, a single detection channel is composed of a scintillation material and a photodetector. The scintillation material absorbs the gamma-energy and emits light photons that produce digital or analog signals in the photodetectors. Nowadays, novel silicon-based photodetectors known as silicon photomultipliers (SiPMs) have been adopted as the next-generation photodetectors for PET applications. In order to further improve the FDG-PET molecular sensitivity and specificity, next-generation instrumentation requires a more accurate time estimation of the detected gamma-photon. Since in time-of-flight (TOF) PET the reconstructed images have an improved signal-to-noise ratio (SNR), which depends on the gamma-photon timemark precision. Additionally, increasing the detection sensitivity improves the statistical quality of information utilized during the image reconstruction process. This thesis introduces the basic concepts of molecular imaging and the key elements of FDG-PET in chapters 1 and 2. A comprehensive theoretical analysis on the utilization of the scintillation light information for gamma-photon timemark estimation is presented in chapter 3. Several estimation methods, such as maximum-likelihood estimation (MLE) and best linear unbiased estimation (BLUE) are presented, as well as a performance comparison with respect to the Cramér-Rao lower bound. Additionally, a detailed study is performed to determine the conditions that allow to reach the Cramér-Rao lower bound. Currently, FDG-PET imaging equipment is not equally available worldwide and one of the reasons is the high costs involved. Often, the design and implementation of TOF-PET instrumentation requires application specific integrated circuit (ASIC) designs, which increases the complexity of the design and required long prototyping phases. Chapter 4 describes the design, implementation, and characterization of TOF-PET instrumentation based on off-the-shelf components, configurable time-to-digital converters (TDCs) implemented on field-programmable gate arrays (FPGAs), and analog SiPMs (A-SiPMs). The proposed solution achieves TOF precision with a full-flexible, fast-prototyping, and ASIC-less designs. Recently, digital SiPMs (D-SiPMs) emerged as a next-generation photodetector for PET applications. In particular, the multichannel digital SiPM (MD-SiPM) architecture integrates single-photon avalanche diodes (SPADs), TDCs, and a readout logic into a monolithic CMOS photodetector. This type of photodetector confines all the measurement devices and circuits within an integrated solution. Therefore, it allows a direct system integration of a large number of channels since only digital signals are required for its operation. However, D-SiPM research and development requires long development and integration cycles due to the high complexity involved. Chapter 5 describes an individual building block and full-system comprehensive analysis of a monolithic array of 18x9 MD-SiPMs. Additionally, it describes in detail the methods developed for multiple TDC systems. In chapter 6, the system integration of MD-SiPMs for building PET detector modules is explained. The challenges of utilizing complex photodetectors for building PET modules, attachment of scintillator matrices, and digital readout strategies are described in a comprehensive manner. Finally, a conclusion of the PET technologies investigated throughout this thesis is given. In addition, an outlook of newer detection methods based on Cherenkov-PET and the corresponding requirements and eventual advantages is discussed.