Small-animal PET and SPECT are essential tools in the development of pharmaceutical drugs, radionuclide therapies, and diagnostic radiotracers. In particular, theranostic tracers, which combine predictive imaging biomarkers with therapeutic agents, have become increasingly important in preclinical research. Imaging these tracers is challenging because their gamma emissions often span a wide energy range, sometimes extending beyond conventional energies, and because activity concentrations can be low. These challenges highlight the need for imaging systems capable of operating over a broad energy range while maintaining high sensitivity and quantitative accuracy.
To address these challenges, the Biomedical Imaging group at TU Delft, in close collaboration with MILabs B.V., has focused on extending the maximum imageable gamma energy in preclinical imaging. This work resulted in the development of the Versatile Emission Computed Tomography (VECTor) system, a fully integrated preclinical PET/SPECT platform employing pinhole collimation for both modalities. VECTor has demonstrated high performance across an extended gamma energy range up to 1 MeV, achieving 0.4 mm resolution in collimated ⁹⁹ᵐTc-SPECT and 0.6 mm resolution in ¹⁸F-PET. Building on this foundation, this simulation-based study investigates software and hardware optimizations to improve the system’s quantitative imaging performance and sensitivity across this wide energy range.
On the software side, several joint reconstruction techniques were evaluated to improve image quality under low-count conditions. Three approaches, Single-Band Joint Reconstruction (SB-JR), Mixed Multi-Band Joint Reconstruction (mMB-JR), and Multi-Band Joint Reconstruction (MB-JR), were assessed using Monte Carlo simulations of resolution phantoms filled with ²²⁵Ac, ²²⁶Ac, or ⁸⁹Zr. Among these methods, MB-JR consistently provided the best image resolution and highest contrast-to-noise ratio across all isotopes and activity levels.
In parallel, hardware optimizations of the gamma camera were explored to improve performance at high energies. Simulations examined the effect of increasing the NaI(Tl) scintillation crystal thickness from the conventional 9.5 mm to 20 mm and 40 mm, combined with optimized light guides and four photomultiplier tube (PMT) geometries. For 511 keV photons, increased crystal thickness yielded substantial sensitivity gains (27% for 20 mm and 57% for 40 mm), with only modest spatial resolution losses when using cost-effective PMTs and potential resolution improvements when smaller PMTs were employed.
Finally, two novel collimator designs optimized for high-energy gamma emissions were evaluated. The Twisted Clustered Pinhole (TCP) collimator retains the clustered geometry of the standard clustered pinhole (CP) design while enabling narrower pinhole opening angles by twisting pinholes around their cluster central axis. For 511 keV (¹⁸F) and 909 keV (⁸⁹Zr) gamma emissions, TCP improved both sensitivity (15.6% for ¹⁸F and 29.4% for ⁸⁹Zr) and spatial resolution compared to CP.
The Super-Cluster (SC) collimator employs a simpler geometry with uniformly distributed pinholes, allowing larger pinhole diameters and a more flexible adjustment of the resolution–sensitivity trade-off. Relative to CP, SC achieved sensitivity gains of up to threefold for ¹⁸F and twofold for ⁸⁹Zr, particularly benefiting low-activity imaging through improved resolution and contrast recovery.
Together, these results demonstrate effective targeted strategies to extend VECTor applicability for high-energy and low-activity preclinical PET/SPECT imaging.

Breast cancer, being the most common cancer among females, is nowadays routinely diagnosed using X-ray mammography. Though this technique has proven its effectiveness in many cases, X-ray mammography has some disadvantages like reduced diagnostic sensitivity for dense breasts, need for strong breast compression and inability to assess tissues at the molecular level. 
Therefore, there is a need for alternative imaging modalities to improve breast cancer diagnosis. One option is breast scintigraphy, which images the distribution of radiolabelled molecules, called tracers, that concentrate in the tumours in breasts with a planar gamma detector. Different tracers react in different physiological processes with tumours. Therefore imaging a specific tracer can reveal the specific pathological process that is specific for a certain kind of breast tumour. Despite the fact that breast scintigraphy has been reported to have improved diagnostic sensitivity in dense breasts compared to X-ray mammography and does not require strong compression, it offers only 2D images and information on the third dimension is thus lost. In this research we proposed a molecular breast tomosynthesis scanner which provides 3D images of the radiotracers in the breast. In the proposed system, the patient would lie prone on a patient bed with a hole in which the breast is inserted. Subsequently, two gamma cameras equipped with multi-pinhole collimators (therefore the technique is called multi-pinhole molecular breast tomosynthesis, MP-MBT) scan the pendant breast from both sides. 
To estimate the performance of MP-MBT, the system was modelled in Monte Carlo simulations in a clinically realistic setting. The results assured us that it was worth building a prototype of MP-MBT to further investigate its imaging capability. Besides, voxelized raytracing (VRT) software developed earlier in our group to accelerate simulations and facilitate system optimisations was validated with the Monte Carlo simulation results. Subsequently, VRT was used in further studies in this project. 
The promising results of MP-MBT simulations partly relied on a gamma detector with high spatial linearity over the whole detector surface. However, conventional gamma detectors used in clinical practice have large dead edges, i.e. about 4 cm from the detector edges is unusable, and a detector with small dead edges would be very expensive, which may make MP-MBT a less competitive technology. Therefore, in order to have a gamma detector suitable for MP-MBT, we came up with a few different designs with NaI(Tl) scintillators and photomultiplier tube (PMT) array readouts and evaluated their performances with Monte Carlo simulations. From the simulation results, we eventually chose a design with a staggered layout of 15 square PMTs, among which two PMTs detected the optical photons from the scintillator through extra-long additional light-guides. This gamma detector was built in our lab, and it turned out to have only about 15 mm dead edge (mainly due to the 12 mm sealing). 
The customised gamma detector was equipped with a lead multi-pinhole collimator design based on previous research. The whole gamma camera was mounted on a robot arm to create a movable scanner. We calibrated the scanner with a point source and scanned a resolution phantom and a breast phantom to evaluate MP-MBT's performance. In the phantom study, the scanner showed the capability of detecting tumours down to 5 mm when a realistic tracer (technetium sestamibi) concentration was administered. 
However, the current prototype is still far from a device that can be used in the clinic and we have found several problems with MP-MBT, especially the noise pattern in the reconstructed images, which should be given special attention in the future research.