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.

Objective. Clustered pinhole (CP) collimation currently supports sub-millimeter resolution imaging up to ∼1 MeV, enabling SPECT of alpha and beta emitters with gamma emissions, simultaneous multi-isotope PET and PET/SPECT, and positron range-free PET. Nonetheless, increasing sensitivity in the original CP designs by enlarging pinhole diameters is limited, as the resulting pinhole opening cones would overlap. Approach. To address this limitation, the use of Super-Cluster (SC) collimation was evaluated in a simulation study. Two SC designs were assessed: a standard configuration (SC-ST) offering a resolution-sensitivity trade-off similar to CP, and a high-sensitivity variant (SC-HS) with larger pinhole diameters to enhance sensitivity. Their performance was compared to CP collimation for 18F at concentrations of 1.0, 0.1, 0.05 MBq ml−1 and ⁸⁹Zr at 2.0, 0.2, 0.1 MBq ml−1, evaluating sensitivity, image resolution, recovery coefficients, and uniformity. Main results. CP and SC-ST showed comparable sensitivity and image resolution. Both resolved 18F rods of 0.9, 1.4, and 1.8 mm at 1.0, 0.1, and 0.05 MBq ml−1, respectively. For ⁸⁹Zr, rods down to 1.0 mm and 1.6 mm were resolved at 2.0 and 0.2 MBq ml−1, but none at 0.1 MBq ml−1. Compared to CP and SC-ST, SC-HS increased sensitivity threefold for 18F and twofold for ⁸⁹Zr. At the highest activity, SC-HS showed slightly reduced resolution for 18F (1.0 mm) and similar for ⁸⁹Zr (1.0 mm). However, it clearly outperformed both other collimators at lower activities, resolving 18F rods of 1.2 and 1.4 mm at 0.1 and 0.05 MBq ml−1, respectively, and ⁸⁹Zr rods of 1.4 and 1.6 mm at 0.2 and 0.1 MBq ml−1. Additionally, SC-HS showed superior contrast recovery. Image uniformity remained consistent across all collimators, confirming effective angular sampling. Significance. The new SC geometry enables high-sensitivity collimation for high gamma energies, improving image quality at low activities. These results demonstrate SC collimation’s strong potential for sensitivity-critical applications.

Objective. Many SPECT and PET radionuclides, along with radionuclides used in targeted alpha or beta therapy and their imaging surrogates have multiple gamma and/or positron emissions. Images of these radionuclides are usually obtained from the photopeak with the most convenient energy and/or highest intensity or by adding counts from different photopeaks. Smart utilization of multiple energy peaks may improve reconstructed images, especially in low-count scans. Approach. We investigate and compare various dual-photopeak joint reconstruction (JR) approaches, namely (i) Single-Band (SB-JR)—projections from two energy windows are summed and reconstructed with a system matrix at a single average energy, (ii) mixed Multi-Band (mMB-JR)—like SB-JR but the system matrix incorporates the element-wise contributions from the photopeak energies, (iii) Multi-Band (MB-JR)—separate projections for each window and separate system matrices at relevant gamma energies are utilized. We evaluate these methods for a multi-pinhole PET-SPECT system (VECTor, MILabs, the Netherlands) using Monte Carlo generated Derenzo phantom projections of 225Ac (218 keV and 440 keV gammas), 226Ac (158 keV and 230 keV gammas) and 89Zr (511 keV annihilation gammas and 909 keV prompt gammas) at three different activity concentrations. A contrast-to-noise ratio (CNR) based quantitative performance analysis was done. Main results. The MB-JR scheme of JR showed superior visual image quality and highest CNRs in almost all cases, across all radionuclides and activity concentrations. The CNR improvement over images acquired from the single best-performing photopeak ranged from 30%–65% for 225Ac, 20%–54% for 226Ac, and 25%–47% for 89Zr, respectively, for the smallest visible rods in the Derenzo phantom. CNR improvements/degradations for the other two methods, mMB-JR and SB-JR, were: for 225Ac, −16%–51% and −21%–51%; for 226Ac, 9%–61% and 0.2%–38%; and for 89Zr, 19%–52% and −3%–16%, respectively. Significance. We believe the proposed image reconstruction methods can enhance SPECT, PET, and PET-SPECT imaging of a wide range of radionuclides that emit gamma’s with multiple energies.

Bremsstrahlung radiation imaging may play an important role in the quantitative evaluation of the spatial-temporal distribution of the β^- radioactive emitters in order to optimize and personalize the methodology and dosage of radiopharmaceuticals in radiometabolic therapy. The present work is an attempt to investigates quantitative bremsstrahlung imaging aspects, using a configurable phantom based experimental apparatus with corresponding simulated model, to highlight critical issues and pitfalls, and to identify, whenever possible, directions to overcome, mitigate or likely take advantage of some of them. Procedure for precise phantom activity determination by portable counter, Monte Carlo fine tuning, definition of figures of merit for the choice of optimal image reconstruction parameters, and correction factors for the activity estimation are some of the main explored details to end up with a preliminary quantitative imaging obtained by simulation-measurement comparison.

Objective. Utilizing prompt gammas in preclinical pinhole-collimated positron emission tomography (PET) avoids image degradation due to positron range blurring and photon down scatter, enables multi-isotope PET and can improve counting statistics for low-abundance positron emitters. This was earlier reported for 124I, 89Zr and simultaneous 124I −18F PET using the VECTor scanner (MILabs, The Netherlands), demonstrating sub-mm resolution despite long positron ranges. The aim of the present study is to investigate if such sub-mm PET imaging is also feasible for a large variety of other isotopes including those with extremely high energy prompt gammas (>1 MeV) or with complex emission spectra of prompt gammas. Approach. We use Monte Carlo simulations to assess achievable image resolutions and uniformity across a broad range of spectrum types and emitted prompt gamma energies (603 keV–2.2 MeV), using 52Mn, 94Tc, 89Zr, 44Sc, 86Y, 72As, 124I, 38K, and 66Ga. Main results. Our results indicate that sub-millimeter resolution imaging may be feasible for almost all isotopes investigated, with the currently used cluster pinhole collimators. At prompt gamma energies of 603 keV of 124I, an image resolution of ∼0.65 mm was achieved, while for emissions at 703, 744, 834, and 909 keV of 94Tc, 52Mn, 72As, and 89Zr, respectively, ∼0.7 mm resolution was obtained. Finally, at ultra-high energies of 1.2 (44Sc) and 1.4 MeV (52Mn) resolutions of ∼0.75 mm and ∼0.8 mm could still be achieved although ring artifacts were observed at the highest energies (1.4 MeV). For 38K (2.2 MeV), an image resolution of 1.2 mm was achieved utilizing its 2.2 MeV prompt emission. Significance. This work shows that current cluster pinhole collimators are suitable for sub-mm resolution prompt PET up till at least 1.4 MeV. This may open up new avenues to developing new tracer applications and therapies utilizing these PET isotopes.

Background: Gamma camera imaging, including single photon emission computed tomography (SPECT), is crucial for research, diagnostics, and radionuclide therapy. Gamma cameras are predominantly based on arrays of photon multipliers tubes (PMTs) that read out NaI(Tl) scintillation crystals. In this way, standard gamma cameras can localize ɣ-rays with energies typically ranging from 30 to 360 keV. In the last decade, there has been an increasing interest towards gamma imaging outside this conventional clinical energy range, for example, for theragnostic applications and preclinical multi-isotope positron emission tomography (PET) and PET-SPECT. However, standard gamma cameras are typically equipped with 9.5 mm thick NaI(Tl) crystals which can result in limited sensitivity for these higher energies. Purpose: Here we investigate to what extent thicker scintillators can improve the photopeak sensitivity for higher energy isotopes while attempting to maintain spatial resolution. Methods: Using Monte Carlo simulations, we analyzed multiple PMT-based configurations of gamma detectors with monolithic NaI (Tl) crystals of 20 and 40 mm thickness. Optimized light guide thickness together with 2-inch round, 3-inch round, 60 × 60 mm² square, and 76 × 76 mm² square PMTs were tested. For each setup, we assessed photopeak sensitivity, energy resolution, spatial, and depth-of-interaction (DoI) resolution for conventional (140 keV) and high (511 keV) energy ɣ using a maximum-likelihood algorithm. These metrics were compared to those of a “standard” 9.5 mm-thick crystal detector with 3-inch round PMTs. Results: Estimated photopeak sensitivities for 511 keV were 27% and 53% for 20 and 40 mm thick scintillators, which is respectively, 2.2 and 4.4 times higher than for 9.5 mm thickness. In most cases, energy resolution benefits from using square PMTs instead of round ones, regardless of their size. Lateral and DoI spatial resolution are best for smaller PMTs (2-inch round and 60 × 60 mm² square) which outperform the more cost-effective larger PMT setups (3-inch round and 76 × 76 mm² square), while PMT layout and shape have negligible (< 10%) effect on resolution. Best spatial resolution was obtained with 60 × 60 mm² PMTs; for 140 keV, lateral resolution was 3.5 mm irrespective of scintillator thickness, improving to 2.8 and 2.9 mm for 511 keV with 20 and 40 mm thick crystals, respectively. Using the 3-inch round PMTs, lateral resolutions of 4.5 and 3.9 mm for 140 keV and of 3.5 and 3.7 mm for 511 keV were obtained with 20 and 40 mm thick crystals respectively, indicating a moderate performance degradation compared to the 3.5 and 2.9 mm resolution obtained by the standard detector for 140 and 511 keV. Additionally, DoI resolution for 511 keV was 7.0 and 5.6 mm with 20 and 40 mm crystals using 60 × 60 mm² square PMTs, while with 3-inch round PMTs 12.1 and 5.9 mm were obtained. Conclusion: Depending on PMT size and shape, the use of thicker scintillator crystals can substantially improve detector sensitivity at high gamma energies, while spatial resolution is slightly improved or mildly degraded compared to standard crystals.

Objective. Advanced pinhole collimation geometries optimized for preclinical high-energy ɣ imaging facilitate applications such as ɑ and ß emitter imaging, simultaneous multi-isotope PET and PET/SPECT, and positron range-free PET. These geometries replace each pinhole with a group of clustered pinholes (CPs) featuring smaller individual pinhole opening angles (POAs), enabling sub-mm resolution imaging up to ∼1 MeV. Further narrowing POAs while retaining field-of-view (FOV) may enhance high-energy imaging but faces geometrical constraints. Here, we detail how the novel twisted CPs (TCPs) address this challenge. Approach. We compared TCP and CP collimator sensitivity at equal system resolution (SR) and SR at matched sensitivity by tuning pinhole diameters for 18F (511 keV) and 89Zr (909 keV). Additionally, simulated Derenzo phantoms at low activity (LA: 12 MBq ml−1) and high activity (HA: 190 MBq ml−1) levels, along with uniformity images, were compared to assess image resolution and uniformity. Main results. At equal SR, TCP increased average central FOV sensitivity by 15.6% for 18F and 29.4% for 89Zr compared to CP. Image resolution was comparable, except for 89Zr at LA, where TCP resolved 0.80 mm diameter rods compared to 0.90 mm for CP. Image uniformity was equivalent for 18F, while for 89Zr TCP granted a 10.4% improvement. For collimators with matched sensitivity, TCP improved SR by 6.6% for 18F and 17.7% for 89Zr while also enhancing image resolution; for 18F, rods distinguished were 0.65 mm (CP) and 0.60 mm (TCP) for HA, and 0.70 mm (CP and TCP) for LA. For 89Zr, image resolutions were 0.75 mm (CP) and 0.65 mm (TCP) for HA, and 0.90 mm (CP) and 0.80 mm (TCP) for LA. Image uniformity with TCP decreased by 18.3% for 18F but improved by 20.1% for 89Zr. Significance. This study suggests that the TCP design has potential to improve high-energy ɣ imaging.