Pandey, Mukesh K.

The present article highlights the important progress made in the last two decades in the fields of molecular imaging and radionuclide therapy. Advancements in radiometal-based positron emission tomography, single photon emission computerized tomography, and radionuclide therapy are illustrated in terms of their production routes and ease of radiolabeling. Applications in clinical diagnostic and radionuclide therapy are considered, including human studies under clinical trials; their current stages of clinical translations and findings are summarized. Because the metalloid astatine is used for imaging and radionuclide therapy, it is included in this review. In regard to radionuclide therapy, both beta-minus (β−) and alpha (α)-emitting radionuclides are discussed by highlighting their production routes, targeted radiopharmaceuticals, and current clinical translation stage.

Abstract Purpose: Melanocortin 1 receptor (MC1R) has been shown in animal models to be a target for effective radionuclide therapy. This first-in-human clinical trial studied the safety and biodistribution of two novel MC1R-targeted imaging tracers designed to support the development of MC1R-targeted alpha particle therapy through image-based identification of MC1R and radiation dosimetry. Imaging was compared to MC1R expression by immunohistochemistry (IHC) of subjects’ melanoma tumors. Methods: Subjects with stage IV melanoma were randomized to receive either [203Pb]VMT01 SPECT/CT imaging followed by [68Ga]VMT02 PET/CT imaging approximately 1 month later, or vice versa in a cross-over design during their normal melanoma treatment course. Patient selection included a positive [18F]FDG PET/CT within 30 days of imaging tracer injection. 555 - 925 mBq of [203Pb]VMT01 was injected IV with imaging performed at 1, 4, and 24 hours. 74 - 277 mBq [68Ga]VMT02 was injected IV and imaging performed dynamically up to 1 hour, and at 2 and 3 hours. Due to an interruption in drug supply, only 3 subjects received [203Pb]VMT01 imaging. Key FDG-avid melanoma lesions were marked and presented to three experienced Radiologists serving as blinded reviewers. The blinded reviewers compared [18F]FDG PET/CT to experimental imaging and scored scans and key lesions on multiple metrics. Imaging positivity was defined as tumor uptake and retention of tracer in ≥ 1 melanoma tumors above background liver activity. Melanoma biopsy tissue was obtained and MC1R IHC performed as available. Results: 7 subjects were enrolled; 6 were imaged and 5 had available pathology. 3 of 6 imaged subjects had MC1R positive tumors via experimental imaging tracers. [68Ga]VMT02 PET/CT at 3 hours led to the best tumor to background ratio, and [203Pb]VMT01 SPECT/CT showed tumor retention at 24 hours. 4 of 5 subjects had positive MC1R staining by IHC. Of the 3 subjects with negative imaging, 2 had positive staining by IHC. Of the 3 subjects with positive imaging, 2 had available biopsies and all stained positive for MC1R by IHC. Conclusion: A subgroup of advanced melanoma patients were identified to express MC1R using new MC1R-targeted imaging agents. Full concordance between imaging and IHC of positive scans, but not with negative scans, suggests that IHC is a more sensitive biomarker detection method. Additional testing is needed to establish frequency of positive MC1R imaging in stage IV melanoma and its correlation to histological findings and treatment outcomes. Preferential tumor retention provides proof-of-concept that the MC1R-targeting therapy trial for [212Pb]VMT01 alpha-emitting therapy will deliver localized radiation to high MC1R expressing tumors as screened by [203Pb]VMT01 or [68Ga]VMT02. Imaging quality is sufficient for subject selection and dosimetry but may exclude subjects with MC1R receptor expression only detectable by IHC. Citation Format: Brenna M. Marks, Matthew Block, Geoffrey B. Johnson, Carrie B. Hruska, Mukesh K. Pandey, Andrew Paulsen, Michael K. Schultz, Michael A. McDonald, Edwin A. Sagastume, Frances L. Johnson. MC1R imaging and histology in the targeted imaging of melanoma for alpha-particle radiotherapy (TIMAR1) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT104.

AbstractGlycogen synthase kinase‐3 α/β is involved in dysregulation of neuronal tau protein in Alzheimer's disease (AD). There is an unmet clinical need for a blood‐brain barrier (BBB) permeable positron emission tomography (PET) probe for imaging of GSK‐3α/β in the brain to understand the pathogenesis of AD. Herein, we synthesized two PET probes, [18F]F‐CNBI and [18F]F‐CNPIFE, and evaluated their BBB permeability and affinity towards GSK‐3α/β. [19F]F‐CNPIFE showed higher in‐vitro binding towards GSK‐3α/β (IC50=19.4±2.5 nM; n=3, for GSK‐3α, IC50=19.4±3.8 nM; n=3, for GSK‐3β) compared to [19F]F‐CNBI (IC50=107.6±26.0 nM; n=4, for GSK‐3α, IC50=105.3±18.2 nM; n=3, for GSK‐3β). [18F]F‐CNPIFE showed 9.5‐fold higher brain uptake than [18F]F‐CNBI, in normal FVB/NJ mice, which was increased by additional 1.5‐fold on co‐administration of [19F]F‐CNPIFE with respect to [18F]F‐CNBI. Overall, [18F]F‐CNPIFE is a promising PET probe for GSK‐3α/β imaging and warrants further evaluation in an AD mouse model.

Abstract 68Ga-DOTATATE is a well-established, positron-emitting, somatostatin receptor–binding radiopharmaceutical. We present an unusual case of transiently increased blood pool uptake of 68Ga-DOTATATE in a patient with well-differentiated stage IV neuroendocrine tumor, with Ki-67 <2% (WHO grade 1) maintained on lanreotide. During serial 68Ga-DOTATATE PET/CT examinations, increased blood pool accumulation of presumably unbound 68Ga was demonstrated, which could impact the Kenning score and lead to a false treatment response assessment.

Abstract Although chimeric antigen receptor T (CART)–cell therapy has been successful in treating certain hematologic malignancies, wider adoption of CART-cell therapy is limited because of minimal activity in solid tumors and development of life-threatening toxicities, including cytokine release syndrome (CRS). There is a lack of a robust, clinically relevant imaging platform to monitor in vivo expansion and trafficking to tumor sites. To address this, we utilized the sodium iodide symporter (NIS) as a platform to image and track CART cells. We engineered CD19-directed and B-cell maturation antigen (BCMA)–directed CART cells to express NIS (NIS+CART19 and NIS+BCMA-CART, respectively) and tested the sensitivity of 18F-TFB-PET to detect trafficking and expansion in systemic and localized tumor models and in a CART-cell toxicity model. NIS+CART19 and NIS+BCMA-CART cells were generated through dual transduction with two vectors and demonstrated exclusive 125I uptake in vitro. 18F-TFB-PET detected NIS+CART cells in vivo to a sensitivity level of 40,000 cells. 18F-TFB-PET confirmed NIS+BCMA-CART-cell trafficking to the tumor sites in localized and systemic tumor models. In a xenograft model for CART-cell toxicity, 18F-TFB-PET revealed significant systemic uptake, correlating with CART-cell in vivo expansion, cytokine production, and development of CRS-associated clinical symptoms. NIS provides a sensitive, clinically applicable platform for CART-cell imaging with PET scan. 18F-TFB-PET detected CART-cell trafficking to tumor sites and in vivo expansion, correlating with the development of clinical and laboratory markers of CRS. These studies demonstrate a noninvasive, clinically relevant method to assess CART-cell functions in vivo.

Background : Zn is implicated as having a role in the formation of calcium oxalate (CaOx) kidney stones. Our studies indicate that Slc39a10 (Zip10) may be important in this process. Zip10 has identifiable sequences in human, dog and fly ( Drosophila ). As we are interested in a translational model of kidney stones, we examined Zip10 from all 3 species. Methods: Zip10 cDNAs were cloned from human & dog (kidney) and fly (whole fly) using gene specific primers and RT‐PCR. Clones were put into a Xenopus oocyte expression vector so that Zip10 function could be measured. Three days post‐injection, oocytes were pre‐incubated in ND96, followed by 30 min in ND96 + 10 μM ZnCl + the PET isotope 63 Zn, with varying pHs and ion concentrations. 63 Zn uptake was measured in each oocyte using a gamma counter. Zip10 oocytes were also checked using electrophysiology (ion selective electrodes & voltage clamping). Results: Zip10 mRNA & protein are found in gut and kidney. In mouse kidney, Zip10 antibodies stained the apical membrane of proximal tubules. All clones transported 63 Zn (nmol/oocyte/hr): hZip10 = 70±8; cZip10= 44 ±7; dZip10= 64 ±8; water = 0.4 ±0.1. These clones seem to be most active at pH 7.5 as uptakes decreased at 5.5 and 8.5. Replacement of either all Cl ‐ (with HCO 3 舉 ) or all Na + (with choline) reduced Zn‐uptake. Electrophysiology revealed no evidence of I or V changes with addition of Zn (electroneutral). Conclusions: Our results indicated that all three Zip10 clones transport Zn 2+ . Understanding the detailed mechanisms of these Zn transporters in oocytes presents the opportunity to better use our Drosophila model in the study of CaOx stone formation and absorption. Grant Funding Source : Supported by DK83007, DK92408

The aim of the present educational review on superparamagnetic iron oxide nanoparticles (SPIONs) is to inform and guide young scientists and students about the potential use and challenges associated with SPIONs. The present review discusses the basic concepts of magnetic resonance imaging (MRI), basic construct of SPIONs, cytotoxic challenges associated with SPIONs, shape and sizes of SPIONs, site-specific accumulation of SPIONs, various methodologies applied to reduce cytotoxicity including coatings with various materials, and application of SPIONs in targeted delivery of chemotherapeutics (Doxorubicin), biotherapeutics (DNA, siRNA), and positron emission tomography (PET) imaging applications.