Head-to-Head Comparison of 68Ga-PSMA-11 with 68Ga-P137 in Patients with Suspected Prostate Cancer.

P137 is a novel oxalyldiaminopropionic acid-urea-based prostate-specific membrane antigen (PSMA) targeting agent. This study compared the uptake patterns of 68Ga-P137 and the FDA-approved PET tracer 68Ga-PSMA-11 for diagnosing prostate cancer (PCa). Sixteen patients suspected of PCa were scanned by 68Ga-PSMA-11 and 68Ga-P137 PET/CT, respectively, followed by prospective analysis. The tumor-to-background ratio was calculated using normal prostate tissue, blood pool, muscle, and urine as backgrounds. Pathology or follow-up results were used to analyze uptake patterns of benign/malignant lesions and various organs. Thirteen patients were diagnosed with PCa and three with benign prostate diseases (BPD). The number and location of primary lesions, lymph node metastasis (LNM) (n = 25), bone metastasis (n = 30), and liver metastasis (n = 3) detected by the two tracers were identical. Maximum standardized uptake value (SUVmax), tumor/normal prostate ratio, as well as semiquantitative miPSMA-ES and PRIMARY diagnostic scores (P all >0.05) showed similar uptake levels of primary lesions between 68Ga-P137 and 68Ga-PSMA-11. Compared to 68Ga-P137, the SUVmax of 68Ga-PSMA-11 was significantly higher for bone metastasis, LNM, and liver metastasis (14.9 ± 7.2 vs 9.1 ± 4.4, 14.4 ± 5.0 vs 7.5 ± 2.4, 13.9 ± 2.0 vs 8.8 ± 2.4, P all <0.05). One-hour postinjection, SUVmax of the duodenum (9.4 ± 2.1 vs 16.2 ± 6.1), kidney (19.4 ± 4.3 vs 45.6 ± 20.9), and urine (14.1 ± 7.1 vs 42.1 ± 25.9) were significantly lower for 68Ga-P137 than for 68Ga-PSMA-11 (P all <0.05), whereas the radioactivity accumulation of blood pool and muscle (3.9 ± 0.5 vs 1.6 ± 0.4, 1.0 ± 0.1 vs 0.6 ± 0.1, P all <0.05) of 68Ga-P137 was significantly higher than 68Ga-PSMA-11. The uptake level of 68Ga-P137 has no significant difference from that of 68Ga-PSMA-11 in prostate primary lesions, and their imaging performances are visually equivalent for both primary and metastatic lesions, despite a higher blood pool and muscle background and a lower uptake in metastatic lesions. Due to the lower urine excretion of 68Ga-P137, primary prostate lesions near the urine can potentially be displayed clearer than 68Ga-PSMA-11.

68Ga-labeled ODAP-Urea-based PSMA agents in prostate cancer: first-in-human imaging of an optimized agent.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a promising target for prostate cancer imaging and therapy. The most commonly used scaffold incorporates a glutamate-urea (Glu-Urea) function. We recently developed oxalyldiaminopropionic acid-urea (ODAP-Urea) PSMA ligands in an attempt to improve upon the pharmacokinetic properties of existing agents. Here, we report the synthesis of an optimized 68Ga-labeled ODAP-Urea-based ligand, [68Ga]Ga-P137, and first-in-human results. METHODS: Twelve ODAP-Urea-based ligands were synthesized and radiolabeled with 68Ga in high radiochemical yield and purity. Their PSMA inhibitory capacities were determined using the NAALADase assay. Radioligands were evaluated in mice-bearing 22Rv1 prostate tumors by microPET. Lead compound [68Ga]Ga-P137 was evaluated for stability, cell uptake, and biodistribution. PET imaging of [68Ga]Ga-P137 was performed in three patients head-to-head compared to [68Ga]Ga-PSMA-617. RESULTS: Ligands were synthesized in 11.1-44.4% yield and > 95% purity. They have high affinity to PSMA (Ki of 0.13 to 5.47 nM). [68Ga]Ga-P137 was stable and hydrophilic. [68Ga]Ga-P137 showed higher uptake than [68Ga]Ga-PSMA-617 in tumor-bearing mice at 6.43 ± 0.98%IA/g vs 3.41 ± 1.31%IA/g at 60-min post-injection. In human studies, the normal organ biodistribution of [68Ga]Ga-P137 was grossly equivalent to that of [68Ga]Ga-PSMA-617 except for within the urinary tract, in which [68Ga]Ga-P137 demonstrated lower uptake. CONCLUSION: The optimized ODAP-Urea-based ligand [68Ga]Ga-P137 can image PSMA in xenograft models and humans, with lower bladder accumulation to the Glu-Urea-based agent, [68Ga]Ga-PSMA-617, in a preliminary, first-in-human study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04560725, Registered 23 September 2020. https://clinicaltrials.gov/ct2/show/NCT04560725.

Feasibility and utility of MRI and dynamic 18F-FDG-PET in an orthotopic organoid-based patient-derived mouse model of endometrial cancer.

BACKGROUND: Pelvic magnetic resonance imaging (MRI) and whole-body positron emission tomography-computed tomography (PET-CT) play an important role at primary diagnostic work-up and in detecting recurrent disease in endometrial cancer (EC) patients, however the preclinical use of these imaging methods is currently limited. We demonstrate the feasibility and utility of MRI and dynamic 18F-fluorodeoxyglucose (FDG)-PET imaging for monitoring tumor progression and assessing chemotherapy response in an orthotopic organoid-based patient-derived xenograft (O-PDX) mouse model of EC. METHODS: 18 O-PDX mice (grade 3 endometrioid EC, stage IIIC1), selectively underwent weekly T2-weighted MRI (total scans = 32), diffusion-weighted MRI (DWI) (total scans = 9) and dynamic 18F-FDG-PET (total scans = 26) during tumor progression. MRI tumor volumes (vMRI), tumor apparent diffusion coefficient values (ADCmean) and metabolic tumor parameters from 18F-FDG-PET including maximum and mean standard uptake values (SUVmax/SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and metabolic rate of 18F-FDG (MRFDG) were calculated. Further, nine mice were included in a chemotherapy treatment study (treatment; n = 5, controls; n = 4) and tumor ADCmean-values were compared to changes in vMRI and cellular density from histology at endpoint. A Mann-Whitney test was used to evaluate differences between groups. RESULTS: Tumors with large tumor volumes (vMRI) had higher metabolic activity (MTV and TLG) in a clear linear relationship (r2 = 0.92 and 0.89, respectively). Non-invasive calculation of MRFDG from dynamic 18F-FDG-PET (mean MRFDG = 0.39 µmol/min) was feasible using an image-derived input function. Treated mice had higher tumor ADCmean (p = 0.03), lower vMRI (p = 0.03) and tumor cellular density (p = 0.02) than non-treated mice, all indicating treatment response. CONCLUSION: Preclinical imaging mirroring clinical imaging methods in EC is highly feasible for monitoring tumor progression and treatment response in the present orthotopic organoid mouse model.

Integrating nanomedicine and imaging.

Biomedical engineering and its associated disciplines play a pivotal role in improving our understanding and management of disease. Motivated by past accomplishments, such as the clinical implementation of coronary stents, pacemakers or recent developments in antibody therapies, disease management now enters a new era in which precision imaging and nanotechnology-enabled therapeutics are maturing to clinical translation. Preclinical molecular imaging increasingly focuses on specific components of the immune system that drive disease progression and complications, allowing the in vivo study of potential therapeutic targets. The first multicentre trials highlight the potential of clinical multimodality imaging for more efficient drug development. In this perspective, the role of integrating engineering, nanotechnology, molecular imaging and immunology to yield precision medicine is discussed.This article is part of the themed issue 'Challenges for chemistry in molecular imaging'.

Cardiac MRI: a Translational Imaging Tool for Characterizing Anthracycline-Induced Myocardial Remodeling.

Cardiovascular side effects of cancer therapeutics are the leading causes of morbidity and mortality in cancer survivors. Anthracyclines (AC) serve as the backbone of many anti-cancer treatment strategies, but dose-dependent myocardial injury limits their use. Cumulative AC exposure can disrupt the dynamic equilibrium of the myocardial microarchitecture while repeated injury and repair leads to myocyte loss, interstitial myocardial fibrosis, and impaired contractility. Although children are assumed to have greater myocardial plasticity, AC exposure at a younger age portends worse prognosis. In older patients, there is lower overall survival once they develop cardiovascular disease. Because aberrations in the myocardial architecture predispose the heart to a decline in function, early detection with sensitive imaging tools is crucial and the implications for resource utilization are substantial. As a comprehensive imaging modality, cardiac magnetic resonance (CMR) imaging is able to go beyond quantification of ejection fraction and myocardial deformation to characterize adaptive microstructural and microvascular changes that are important to myocardial tissue health. Herein, we describe CMR as an established translational imaging tool that can be used clinically to characterize AC-associated myocardial remodeling.

First-in-Humans Evaluation of Safety and Dosimetry of 64Cu-LLP2A for PET Imaging.

There remains an unmet need for molecularly targeted imaging agents for multiple myeloma (MM). The integrin very late antigen 4 (VLA4), is differentially expressed in malignant MM cells and in pathogenic inflammatory microenvironmental cells. [64Cu]Cu-CB-TE1A1P-LLP2A (64Cu-LLP2A) is a VLA4-targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated the safety and human radiation dosimetry of 64Cu-LLP2A for potential use in MM patients. Methods: A single-dose [natCu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed on CD-1 (Hsd:ICR) male and female mice. 64Cu-LLP2A was synthesized in accordance with good-manufacturing-practice-compliant procedures. Three MM patients and six healthy participants underwent 64Cu-LLP2A-PET/CT or PET/MRI at up to 3 time points to help determine tracer biodistribution, pharmacokinetics, and radiation dosimetry. Time-activity curves were plotted for each participant. Mean organ-absorbed doses and effective doses were calculated using the OLINDA software. Tracer bioactivity was evaluated via cell-binding assays, and metabolites from human blood samples were analyzed with analytic radio-high-performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry. Results: A 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level). Time-activity curves from human imaging data showed rapid tracer clearance from blood via the kidneys and bladder. The effective dose of 64Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and the spleen had the highest organ uptake, 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated the highest residence time. Image quality analysis supports an early imaging time (4-5 h after injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all human studies (82.42% ± 13.47%). Blood metabolism studies confirmed a stable product peak (>90%) up to 1 h after injection of the radiopharmaceutical. No clinical or laboratory adverse events related to 64Cu-LLP2A were observed in the human participants. Conclusion: 64Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.

Improved synthesis of [18F] fallypride and characterization of a Huntington's disease mouse model, zQ175DN KI, using longitudinal PET imaging of D2/D3 receptors.

PURPOSE: Dopamine receptors are involved in pathophysiology of neuropsychiatric diseases, including Huntington's disease (HD). PET imaging of dopamine D2 receptors (D2R) in HD patients has demonstrated 40% decrease in D2R binding in striatum, and D2R could be a reliable quantitative target to monitor disease progression. A D2/3R antagonist, [18F] fallypride, is a high-affinity radioligand that has been clinically used to study receptor density and occupancy in neuropsychiatric disorders. Here we report an improved synthesis method for [18F]fallypride. In addition, high molar activity of the ligand has allowed us to apply PET imaging to characterize D2/D3 receptor density in striatum of the recently developed zQ175DN knock-in (KI) mouse model of HD. METHODS: We longitudinally characterized in vivo [18F] fallypride -PET imaging of D2/D3 receptor densities in striatum of 9 and 12 month old wild type (WT) and heterozygous (HET) zQ175DN KI mouse. Furthermore, we verified the D2/D3 receptor density in striatum with [3H] fallypride autoradiography at 12 months of age. RESULTS: We implemented an improved synthesis method for [18F] fallypride to yield high molar activity (MA, 298-360 GBq/µmol) and good reproducibility. In the HET zQ175DN KI mice, we observed a significant longitudinal decrease in binding potential (BPND) (30.2%, p < 0.001, 9 months of age and 51.6%, p < 0.001, 12 months of age) compared to WT littermates. No mass effect was observed when the MA of [18F] fallypride was > 100 GBq/µmol at the time of injection. Furthermore, the decrease of D2/D3 receptor density in striatum in HET zQ175DN KI was consistent using [3H] fallypride autoradiography. CONCLUSIONS: We observed a significant decrease in D2/D3R receptor densities in the striatum of HET zQ175DN KI mice compared to WT mice at 9 and 12 months of age. These results are in line with clinical findings in HD patients, suggesting [18F] fallypride PET imaging has potential as a quantitative translational approach to monitor disease progression in preclinical studies.

Tissue oxygen saturation predicts response to breast cancer neoadjuvant chemotherapy within 10 days of treatment.

Ideally, neoadjuvant chemotherapy (NAC) assessment should predict pathologic complete response (pCR), a surrogate clinical endpoint for 5-year survival, as early as possible during typical 3- to 6-month breast cancer treatments. We introduce and demonstrate an approach for predicting pCR within 10 days of initiating NAC. The method uses a bedside diffuse optical spectroscopic imaging (DOSI) technology and logistic regression modeling. Tumor and normal tissue physiological properties were measured longitudinally throughout the course of NAC in 33 patients enrolled in the American College of Radiology Imaging Network multicenter breast cancer DOSI trial (ACRIN-6691). An image analysis scheme, employing z-score normalization to healthy tissue, produced models with robust predictions. Notably, logistic regression based on z-score normalization using only tissue oxygen saturation (StO2) measured within 10 days of the initial therapy dose was found to be a significant predictor of pCR (AUC = 0.92; 95% CI: 0.82 to 1). This observation suggests that patients who show rapid convergence of tumor tissue StO2 to surrounding tissue StO2 are more likely to achieve pCR. This early predictor of pCR occurs prior to reductions in tumor size and could enable dynamic feedback for optimization of chemotherapy strategies in breast cancer.

Translational Molecular Nuclear Cardiology.

Increased rollout and availability of preclinical imaging provides a foundation for development of novel molecular nuclear imaging agents. The current armamentarium of radiotracers available for nuclear cardiology allows for the interrogation of critical molecular processes involved in a myriad of cardiovascular disorders, including altered metabolism, ventricular remodeling, sympathetic neuronal activation, and systemic inflammation. Effective translational molecular imaging requires coordination of clinical need with tracer development and molecular biology, leading to the identification of ideal translational imaging compounds.