Monika Kvassheim | Theragnostic Imaging

Therapeutic evaluation of [212Pb]Pb-AB001 and [177Lu]Lu-PSMA-617 in a mouse model of disseminated prostate cancer

Wed, 21 May 2025 00:00:00 +0000

Metastatic castration-resistant prostate cancer (mCRPC) frequently leads to bone and soft tissue metastases, leading to poor prognosis. The beta-emitting radioligand [¹⁷⁷Lu]Lu-PSMA-617 targets the prostate-specific membrane antigen (PSMA) and may be less efficient against micrometastatic disease. The alpha-emitting radioligand [²¹²Pb]Pb-AB001 could offer enhanced treatment by delivering high energy over a short range. This study compared the efficacy of [²¹²Pb]Pb-AB001 and [¹⁷⁷Lu]Lu-PSMA-617 in a mouse model of disseminated prostate cancer. Binding and internalisation of radioligands were evaluated in PC-3 PIP-luc cells. A mouse model was established by intracardiac injection of these cells. Treatments with 0.24‒1.0 MBq [²¹²Pb]Pb-AB001 or 22‒66 MBq [¹⁷⁷Lu]Lu-PSMA-617 were initiated 7 d post-cell inoculation. Metastatic burden was measured using bioluminescence imaging, and PSMA-targeted uptake was determined with [¹⁸F]F-PSMA-1007 µPET/µCT. Gamma-autoradiography evaluated [²¹²Pb]Pb-AB001 distribution, and bone metastases were identified by radiography. Both radioligands displayed comparable in vitro binding. In vivo studies revealed metastatic formation in clinically relevant organs. µPET/µCT demonstrated increased [¹⁸F]F-PSMA-1007 uptake in metastases, matching the bioluminescence imaging results. Focal [²¹²Pb]Pb-AB001 distribution in the metastatic xenograft indicated heterogeneously distributed micrometastases in the organs. A median survival up to 47 d was achieved with [²¹²Pb]Pb-AB001, compared to 25 d for controls and 27 d for [¹⁷⁷Lu]Lu-PSMA-617. An activity-dependent reduction in bone metastases was observed for [¹⁷⁷Lu]Lu-PSMA-617, while no bone lesions were detected in [²¹²Pb]Pb-AB001-treated mice. [²¹²Pb]Pb-AB001 showed significant efficacy against micrometastases and advantages over [¹⁷⁷Lu]Lu-PSMA-617 in preventing or treating early bone metastases for the investigated injected activities. This implies clinical potential for treating mCRPC, including patients at risk of early metastatic disease, but further studies including dosimetry and toxicity analyses are required with regards to activity levels.

First-in-Human Phase 0 Study of AB001, a Prostate-Specific Membrane Antigen-Targeted 212Pb Radioligand, in Patients with Metastatic Castration-Resistant Prostate Cancer

Thu, 01 May 2025 00:00:00 +0000

AB001, a prostate-specific membrane antigen (PSMA)-targeted small molecule labeled with the in vivo-generating α-emitter ²¹²Pb, was investigated in a phase 0 trial in patients with metastatic castration-resistant prostate cancer (mCRPC). The primary objective was to explore the feasibility of γ-camera imaging to assess biodistribution and uptake in metastatic lesions.

Methods: Three patients with progressive mCRPC and Eastern Cooperative Oncology Group performance status 1 were included, having prostate-specific antigen levels of 0.44, 0.75, and 15 µg/L. All had at least 3 PSMA-expressing metastatic lesions, with an SUV_max range of 10.1-77.4 on PSMA PET. Each patient received a microdose of 9.4 ± 0.3 MBq of AB001 intravenously. Planar γ-camera and SPECT/CT imaging was scheduled 1-3 h and 16-24 h after administration. Whole-body clearance was assessed with NaI probe measurements. Activity of ²¹²Pb in whole blood and plasma was measured to investigate clearance from blood and in vivo stability of the ligand. Safety, tolerability, and efficacy biomarkers (prostate-specific antigen, alkaline phosphatase) were followed for 28 d.

Results: AB001 uptake in the lesion with the highest PSMA expression, a retrocaval lymph node metastasis with a short-axis diameter of 11 mm, was visualized on SPECT. Uptake of AB001 was not clearly demonstrated for other metastatic lesions, possibly because of the lower PSMA expression of these metastases on PSMA PET, combined with the administered AB001 microdose and imaging system limitations. Kidney, urinary bladder with contents, and liver uptake of AB001 were clearly distinguishable from adjacent tissue, and the blood pool content was seen. Salivary glands were not visualized. Blood analyses indicated stability of AB001 after injection, and whole-body probe measurements demonstrated an effective half-life of 8 h. There were no complications related to injection of AB001 or adverse reactions during follow-up. As expected for a phase 0 study, there was no indication of therapeutic effects as assessed by prostate-specific antigen and alkaline phosphatase.

Conclusion: The ²¹²Pb-based radioligand AB001 was safely administered to mCRPC patients. γ-camera imaging of AB001 was feasible, even at a microdose, and demonstrated metastatic targeting, albeit for only 1 lesion. The promising biodistribution and clearance encourage further clinical investigation.

Twisted clustered pinhole collimation for improved high-energy preclinical SPECT/PET

Wed, 13 Nov 2024 00:00:00 +0000

Objective.Advanced pinhole collimation geometries optimized for preclinical high-energyɣimaging facilitate applications such asɑandßemitter 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 for¹⁸F (511 keV) and⁸⁹Zr (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% for¹⁸F and 29.4% for⁸⁹Zr compared to CP. Image resolution was comparable, except for⁸⁹Zr at LA, where TCP resolved 0.80 mm diameter rods compared to 0.90 mm for CP. Image uniformity was equivalent for¹⁸F, while for⁸⁹Zr TCP granted a 10.4% improvement. For collimators with matched sensitivity, TCP improved SR by 6.6% for¹⁸F and 17.7% for⁸⁹Zr while also enhancing image resolution; for¹⁸F, rods distinguished were 0.65 mm (CP) and 0.60 mm (TCP) for HA, and 0.70 mm (CP and TCP) for LA. For⁸⁹Zr, 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% for¹⁸F but improved by 20.1% for⁸⁹Zr.Significance.This study suggests that the TCP design has potential to improve high-energyɣimaging.

Imaging of 212Pb in mice with a clinical SPECT/CT

Mon, 21 Aug 2023 00:00:00 +0000

²¹²Pb is a promising radionuclide for targeted alpha therapy. Here, the feasibility of visualising the tumour uptake and biodistribution of ²¹²Pb-NG001 in mice with a clinical SPECT/CT scanner was investigated. A mouse phantom with ²¹²Pb was imaged with a clinical- and a preclinical SPECT/CT scanner. Different acquisition and reconstruction settings were investigated on the clinical system (Siemens Symbia Intevo Bold). Two athymic nude mice carrying PC-3 PIP prostate cancer tumours of 235-830 μl received 1.44 MBq of ²¹²Pb-NG001 and were imaged 2, 6, and 24 h post-injection on the clinical SPECT/CT with a Medium Energy collimator and a 40% energy window centred on 79 keV. All acquisition times were 30 min, except the mouse imaging 24 h post-injection which was 60 min. After the final imaging, the organs were harvested and measured on a gamma counter to give an indication of how much activity was present in organs of interest at the last imaging time point. Four volumes in the mouse phantom of ~ 300 μl with 246-303 kBq/ml of ²¹²Pb were distinguishable on images acquired with the clinical SPECT/CT with a high number of reconstruction updates. With the preclinical SPECT, the same volumes were easily distinguished with 49 kBq/ml of ²¹²Pb. Clinical SPECT/CT images of the mice revealed uptake in tumours and bladders 2 h after injection and in tumours containing down to approximately 15 kBq/ml at 6 and 24 h after injection. Although the preclinical scanner should be used preferentially in biodistribution studies in mice, the clinical SPECT/CT confirmed uptake in small volumes (e.g. ~ 300 μl volume with ~ 250 kBq/ml). Regardless of system, the resolution and sensitivity limits should be carefully determined, otherwise false negative or too low uptakes can be wrongly interpreted.

Optimized SPECT Imaging of 224Ra α-Particle Therapy by 212Pb Photon Emissions

Sat, 01 Jul 2023 00:00:00 +0000

In preparation for an α-particle therapy trial using 1-7 MBq of ²²⁴Ra, the feasibility of tomographic SPECT/CT imaging was of interest. The nuclide decays in 6 steps to stable ²⁰⁸Pb, with ²¹²Pb as the principle photon-emitting nuclide. ²¹²Bi and ²⁰⁸Tl emit high-energy photons up to 2,615 keV. A phantom study was conducted to determine the optimal acquisition and reconstruction protocol.

Methods: The spheres of a body phantom were filled with a ²²⁴Ra-RaCl₂ solution, and the background compartment was filled with water. Images were acquired on a SPECT/CT system. In addition, 30-min scans were acquired for 80- and 240-keV emissions, using triple-energy windows, with both medium-energy and high-energy collimators. Images were acquired at 90-95 and 29-30 kBq/mL, plus an explorative 3-min acquisition at 20 kBq/mL (using only the optimal protocol). Reconstructions were performed with attenuation correction only, attenuation plus scatter correction, 3 levels of postfiltering, and 24 levels of iterative updates. Acquisitions and reconstructions were compared using the maximum value and signal-to-scatter peak ratio for each sphere. Monte Carlo simulations were performed to examine the contributions of key emissions.

Results: Secondary photons of the 2,615-keV ²⁰⁸Tl emission produced in the collimators make up most of the acquired energy spectrum, as revealed by Monte Carlo simulations, with only a small fraction (3%-6%) of photons in each window providing useful information for imaging. Still, decent image quality is possible at 30 kBq/mL, and nuclide concentrations are imageable down to approximately 2-5 kBq/mL. The overall best results were obtained with the 240-keV window, medium-energy collimator, attenuation and scatter correction, 30 iterations and 2 subsets, and a 12-mm gaussian postprocessing filter. However, all combinations of the applied collimators and energy windows were capable of producing adequate results, even though some failed to reconstruct the 2 smallest spheres.

Conclusion: SPECT/CT imaging of ²²⁴Ra in equilibrium with daughters is possible, with sufficient image quality to provide clinical utility for the current trial of intraperitoneally administrated activity. A systematic scheme for optimization was designed to select acquisition and reconstruction settings.

Correction to: Quantitative SPECT/CT imaging of lead-212: a phantom study

Mon, 10 Oct 2022 00:00:00 +0000

No abstract available

Radionuclides for Targeted Therapy: Physical Properties

Thu, 25 Aug 2022 00:00:00 +0000

A search in PubMed revealed that 72 radionuclides have been considered for molecular or functional targeted radionuclide therapy. As radionuclide therapies increase in number and variations, it is important to understand the role of the radionuclide and the various characteristics that can render it either useful or useless. This review focuses on the physical characteristics of radionuclides that are relevant for radionuclide therapy, such as linear energy transfer, relative biological effectiveness, range, half-life, imaging properties, and radiation protection considerations. All these properties vary considerably between radionuclides and can be optimised for specific targets. Properties that are advantageous for some applications can sometimes be drawbacks for others; for instance, radionuclides that enable easy imaging can introduce more radiation protection concerns than others. Similarly, a long radiation range is beneficial in targets with heterogeneous uptake, but it also increases the radiation dose to tissues surrounding the target, and, hence, a shorter range is likely more beneficial with homogeneous uptake. While one cannot select a collection of characteristics as each radionuclide comes with an unchangeable set, all the 72 radionuclides investigated for therapy-and many more that have not yet been investigated-provide numerous sets to choose between.

Quantitative SPECT/CT imaging of lead-212: a phantom study

Thu, 04 Aug 2022 00:00:00 +0000

Lead-212 (²¹²Pb) is a promising radionuclide for targeted therapy, as it decays to α-particle emitter bismuth-212 (²¹²Bi) via β-particle emission. This extends the problematic short half-life of ²¹²Bi. In preparation for upcoming clinical trials with ²¹²Pb, the feasibility of quantitative single photon-emission computed tomography/computed tomography (SPECT/CT) imaging of ²¹²Pb was studied, with the purpose to explore the possibility of individualised patient dosimetric estimation. Both acquisition parameters (combining two different energy windows and two different collimators) and iterative reconstruction parameters (varying the iterations x subsets between 10 × 1, 15 × 1, 30 × 1, 30 × 2, 30 × 3, 30 × 4, and 30 × 30) were investigated to evaluate visual quality and quantitative uncertainties based on phantom images. Calibration factors were determined using a homogeneous phantom and were stable when the total activity imaged exceeded 1 MBq for all the imaging protocols studied, but they increased sharply as the activity decayed below 1 MBq. Both a 20% window centred on 239 keV and a 40% window on 79 keV, with dual scatter windows of 5% and 20%, respectively, could be used. Visual quality at the lowest activity concentrations was improved with the High Energy collimator and the 79 keV energy window. Fractional uncertainty in the activity quantitation, including uncertainties from calibration factors and small volume effects, in spheres of 2.6 ml in the NEMA phantom was 16-21% for all protocols with the 30 × 4 filtered reconstruction except the High Energy collimator with the 239 keV energy window. Quantitative analysis was possible both with and without filters, but the visual quality of the images improved with a filter. Only minor differences were observed between the imaging protocols which were all determined suitable for quantitative imaging of ²¹²Pb. As uncertainties generally decreased with increasing iterative updates in the reconstruction and recovery curves did not converge with few iterations, a high number of reconstruction updates are recommended for quantitative imaging.