Rapid progress has been made to identify and study the causative agent leading to coronavirus disease 2019 (COVID‐19) but many questions including who is most susceptible and what determines severity remain unanswered. Angiotensin‐converting enzyme 2 (ACE2) is a key factor in the infection process of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). In this study, molecularly specific positron emission tomography imaging agents for targeting ACE2 are first developed, and these novel agents are evaluated in vitro, in preclinical model systems, and in a first‐in‐human translational ACE2 imaging of healthy volunteers and a SARS‐CoV‐2 recovered patient (NCT04422457). ACE2 expression levels in different organs in live subjects are quantitatively delineated and observable differences are measured in the patient recovered from COVID‐19. Surprising sites of uptake in the breast, reproductive system and very low uptake in pulmonary tissues are reported. This novel method can add a unique tool to facilitate SARS‐CoV‐2 related research and improve understanding of this enigmatic disease. Molecular imaging provides quantitative annotation of ACE2, the SARS‐CoV‐2 entry receptor, to noninvasively monitor organs impacted by the COVID‐19.

Background 223 Ra imaging is crucial to evaluate the successfulness of the therapy of bone metastasis of castration-resistant prostate cancer (CRPC). The goals of this study were to establish a quantitative tomographic 223 Ra imaging protocol with clinically achievable conditions, as well as to investigate its usefulness and limitations. We performed several experiments using the Infinia Hawkeye 4 gamma camera (GE) and physical phantoms in order to assess the optimal image acquisition and reconstruction parameters, such as the windows setting, as well as the iteration number and filter of the reconstruction algorithm. Then, based on the MIRD pamphlet 23, we used a NEMA phantom and an anthropomorphic TORSO® phantom to calibrate the gamma camera and investigate the accuracy of quantification. Results Experiences showed that the 85 keV ± 20%, 154 keV ± 10%, and 270 keV ± 10% energy windows are the most suitable for 223 Ra imaging. The study with the NEMA phantom showed that the OSEM algorithm with 2 iterations, 10 subsets, and the Butterworth filter offered the best compromise between contrast and noise. Moreover, the calibration factors for different sphere sizes (26.5 ml, 11.5 ml, and 5.6 ml) were constant for 223 Ra concentrations ranging between 6.5 and 22.8 kBq/ml. The values found are 73.7 cts/s/MBq, 43.8 cts/s/MBq, and 43.4 cts/s/MBq for 26.5 ml, 11.5 ml, and 5.6 ml sphere, respectively. For concentration lower than 6.5 kBq/ml, the calibration factors exhibited greater variability pointing out the limitations of SPECT/CT imaging for quantification. By the use of a TORSO® phantom, we simulated several tumors to normal tissue ratios as close as possible to clinical conditions. Using the calibration factors obtained with the NEMA phantom, for 223 Ra concentrations higher than 8 kBq/ml, we were able to quantify the activity with an error inferior to 18.8% in a 5.6 ml lesion. Conclusions Absolute quantitative 223 Ra SPECT imaging appears feasible once the dimension of the target is determined. Further evaluation should be needed to apply the calibration factor-based quantitation to clinical 223 Ra SPECT/CT imaging. This will open the possibility for patient-specific 223 Ra treatment planning and therapeutic outcome prediction in patients.

Single-photon emission-computed tomography (SPECT) provides a mechanism to estimate regional isotope uptake in lesions and at-risk organs after administration of α-particle-emitting radiopharmaceutical therapies (α-RPTs). However, this estimation task is challenging due to the complex emission spectra, the very low number of detected counts (∼20 times lower than in conventional SPECT), the impact of stray-radiation-related noise at these low counts, and the multiple image-degrading processes in SPECT. The conventional reconstruction-based quantification methods are observed to be erroneous for α-RPT SPECT. To address these challenges, we developed a low-count quantitative SPECT (LC-QSPECT) method that directly estimates the regional activity uptake from the projection data (obviating the reconstruction step), compensates for stray-radiation-related noise, and accounts for the radioisotope and SPECT physics, including the isotope spectra, scatter, attenuation, and collimator-detector response, using a Monte Carlo-based approach. The method was validated in the context of 3-D SPECT with 223 Ra, a commonly used radionuclide for α-RPT. Validation was performed using both realistic simulation studies, including a virtual clinical trial, and synthetic and 3-D-printed anthropomorphic physical-phantom studies. Across all studies, the LC-QSPECT method yielded reliable regional-uptake estimates and outperformed the conventional ordered subset expectation-maximization (OSEM)-based

Purpose: Most patients with prostate cancer treated with androgen receptor (AR) signaling inhibitors develop therapeutic resistance due to restoration of AR functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized mAb specifically targeting free PSA (KLK3).Experimental Design: LNCaP-AR (LNCaP with overexpression of wildtype AR) xenografts (NSG mice) and KLK3_Hi-Myc transgenic mice were imaged with 89 Zr-or treated with 90 Y-or 225 Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma counting, PET, autoradiography, and microscopy. Therapeutic efficacy of [ 225 Ac]hu5A10 and [ 90 Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [ 89 Zr]hu5A10 in nonhuman primates (NHP) were determined using PET. Results: Biodistribution of radiolabeled hu5A10 constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [ 90 Y]/[ 225 Ac]hu5A10 effectively reduced tumor burden and prolonged survival (P ≤ 0.0054). Effects of [ 90 Y]hu5A10 were more immediate than [ 225 Ac]hu5A10 (TTN, P < 0.0001) but less sustained (TTP, P < 0.0001). Complete responses were observed in 7 of 18 [ 225 Ac]hu5A10 and 1 of 9 mice [ 90 Y]hu5A10. Pharmacokinetics of [ 89 Zr]hu5A10 were consistent between NHPs and comparable with those in mice. [ 89 Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period.Conclusions: We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse prostate cancer models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSAexpressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating prostate cancer.

Rationale: Alpha particle emitting radiopharmaceuticals are generating considerable interest for the treatment of disseminated metastatic disease. Molecular imaging of the distribution of these agents is critical to safely and effectively maximize the clinical potential of this emerging drug class. The present studies aim to investigate the feasibility and limitations of quantitative SPECT for 223 Ra, 225 Ac and 227 Th. Methods: Three state-of-the-art SPECT/CT systems were investigated: the GE Discovery NM/CT 670, the GE Optima NM/CT 640, and the Siemens Symbia T6. A series of phantoms, including the NEMA IEC Body phantom, were used to compare and calibrate each camera. Additionally, anthropomorphic physical tumor and vertebrae phantoms were developed and imaged to evaluate the quantitative imaging protocol. Results: This work describes and validates a methodology to calibrate each clinical system. The efficiency of each gamma camera was analyzed and compared. Using the calibration factors obtained with the NEMA phantom, we were able to quantify the activity in 3D-printed tissue phantoms with an error of 2.1%, 3.5% and 11.8% for 223 Ra, 225 Ac, and 227 Th, respectively. Conclusion: The present study validates that quantitative SPECT/CT imaging of 223 Ra, 225 Ac, and 227 Th is achievable but that careful considerations for camera configuration are required. These results will aid in future implementation of SPECT-based patient studies and will help to identify the limiting factors for accurate image-based quantification with alpha particle emitting radionuclides.