Interrogating the Theranostic Capacity of a MUC16-Targeted Antibody for Ovarian Cancer.

Aberrantly expressed glycans on mucins such as mucin-16 (MUC16) are implicated in the biology that promotes ovarian cancer (OC) malignancy. Here, we investigated the theranostic potential of a humanized antibody, huAR9.6, targeting fully glycosylated and hypoglycosylated MUC16 isoforms. Methods: In vitro and in vivo targeting of the diagnostic radiotracer [89Zr]Zr-DFO-huAR9.6 was investigated via binding experiments, immuno-PET imaging, and biodistribution studies on OC mouse models. Ovarian xenografts were used to determine the safety and efficacy of the therapeutic version, [177Lu]Lu-CHX-A″-DTPA-huAR9.6. Results: In vivo uptake of [89Zr]Zr-DFO-huAR9.6 supported in vitro-determined expression levels: high uptake in OVCAR3 and OVCAR4 tumors, low uptake in OVCAR5 tumors, and no uptake in OVCAR8 tumors. Accordingly, [177Lu]Lu-CHX-A″-DTPA-huAR9.6 displayed strong antitumor effects in the OVCAR3 model and improved overall survival in the OVCAR3 and OVCAR5 models in comparison to the saline control. Hematologic toxicity was transient in both models. Conclusion: PET imaging of OC xenografts showed that [89Zr]Zr-DFO-huAR9.6 delineated MUC16 expression levels, which correlated with in vitro results. Additionally, we showed that [177Lu]Lu-CHX-A″-DTPA-huAR9.6 displayed strong antitumor effects in highly MUC16-expressing tumors. These findings demonstrate great potential for 89Zr- and 177Lu-labeled huAR9.6 as theranostic tools for the diagnosis and treatment of OC.

Evaluating CD133 as a Radiotheranostic Target in Small-Cell Lung Cancer.

Despite decades of work, small-cell lung cancer (SCLC) remains a frustratingly recalcitrant disease. Both diagnosis and treatment are challenges: low-dose computed tomography (the approved method used for lung cancer screening) is unable to reliably detect early SCLC, and the malignancy's 5 year survival rate stands at a paltry 7%. Clearly, the development of novel diagnostic and therapeutic tools for SCLC is an urgent, unmet need. CD133 is a transmembrane protein that is expressed at low levels in normal tissue but is overexpressed by a variety of tumors, including SCLC. We previously explored CD133 as a biomarker for a novel autoantibody-to-immunopositron emission tomography (PET) strategy for the diagnosis of SCLC, work that first suggested the promise of the antigen as a radiotheranostic target in the disease. Herein, we report the in vivo validation of a pair of CD133-targeted radioimmunoconjugates for the PET imaging and radioimmunotherapy of SCLC. To this end, [89Zr]Zr-DFO-αCD133 was first interrogated in a trio of advanced murine models of SCLC─i.e., orthotopic, metastatic, and patient-derived xenografts─with the PET probe consistently producing high activity concentrations (>%ID/g) in tumor lesions combined with low uptake in healthy tissues. Subsequently, a variant of αCD133 labeled with the ß-emitting radiometal 177Lu─[177Lu]Lu-DTPA-A″-CHX-αCD133─was synthesized and evaluated in a longitudinal therapy study in a subcutaneous xenograft model of SCLC, ultimately revealing that treatment with a dose of 9.6 MBq of the radioimmunoconjugate produced a significant increase in median survival compared to a control cohort. Taken together, these data establish CD133 as a viable target for the nuclear imaging and radiopharmaceutical therapy of SCLC.

MIRD Pamphlet No. 29: MIRDy90-A 90Y Research Microsphere Dosimetry Tool.

90Y-microsphere radioembolization has become a well-established treatment option for liver malignancies and is one of the first U.S. Food and Drug Administration-approved unsealed radionuclide brachytherapy devices to incorporate dosimetry-based treatment planning. Several different mathematical models are used to calculate the patient-specific prescribed activity of 90Y, namely, body surface area (SIR-Spheres only), MIRD single compartment, and MIRD dual compartment (partition). Under the auspices of the MIRDsoft initiative to develop community dosimetry software and tools, the body surface area, MIRD single-compartment, MIRD dual-compartment, and MIRD multicompartment models have been integrated into a MIRDy90 software worksheet. The worksheet was built in MS Excel to estimate and compare prescribed activities calculated via these respective models. The MIRDy90 software was validated against available tools for calculating 90Y prescribed activity. The results of MIRDy90 calculations were compared with those obtained from vendor and community-developed tools, and the calculations agreed well. The MIRDy90 worksheet was developed to provide a vetted tool to better evaluate patient-specific prescribed activities calculated via different models, as well as model influences with respect to varying input parameters. MIRDy90 allows users to interact and visualize the results of various parameter combinations. Variables, equations, and calculations are described in the MIRDy90 documentation and articulated in the MIRDy90 worksheet. The worksheet is distributed as a free tool to build expertise within the medical physics community and create a vetted standard for model and variable management.

212Pb-Pretargeted Theranostics for Pancreatic Cancer.

Although pancreatic ductal adenocarcinoma (PDAC) is associated with limited treatment options and poor patient outcomes, targeted α-particle therapy (TAT) represents a promising development in the field. TAT shows potential in treating metastatic cancers, including those that have become resistant to conventional treatments. Among the most auspicious radionuclides stands the in vivo α-generator 212Pb. Combined with the imaging-compatible radionuclide 203Pb, this theranostic match is a promising modality rapidly translating into the clinic. Methods: Using the pretargeting approach between a radiolabeled 1,2,4,5-tetrazine (Tz) tracer and a trans-cyclooctene (TCO) modified antibody, imaging and therapy with radiolead were performed on a PDAC tumor xenograft mouse model. For therapy, 3 cohorts received a single administration of 1.1, 2.2, or 3.7 MBq of the pretargeting agent, [212Pb]Pb-DO3A-PEG7-Tz, whereby administered activity levels were guided by dosimetric analysis. Results: The treated mice were holistically evaluated; minimal-to-mild renal tubular necrosis was observed. At the same time, median survival doubled for the highest-dose cohort (10.7 wk) compared with the control cohort (5.1 wk). Conclusion: This foundational study demonstrated the feasibility and safety of pretargeted TAT with 212Pb in PDAC while considering dose limitations and potential adverse effects.

MIB Guides: Preclinical Radiopharmaceutical Dosimetry.

Preclinical dosimetry is essential for guiding the design of animal radiopharmaceutical biodistribution, imaging, and therapy experiments, evaluating efficacy and/or toxicities in such experiments, ensuring compliance with ethical standards for animal research, and, perhaps most importantly, providing reasonable initial estimates of normal-organ doses in humans, required for clinical translation of new radiopharmaceuticals. This MIB Guide provides a basic protocol for obtaining preclinical dosimetry estimates with organ-level dosimetry software.

Engineering CAR-T cells for radiohapten capture in imaging and radioimmunotherapy applications.

Rationale: The in vivo dynamics of CAR-T cells remain incompletely understood. Novel methods are urgently needed to longitudinally monitor transferred cells non-invasively for biodistribution, functionality, proliferation, and persistence in vivo and for improving their cytotoxic potency in case of treatment failure. Methods: Here we engineered CD19 CAR-T cells ("Thor"-cells) to express a membrane-bound scFv, huC825, that binds DOTA-haptens with picomolar affinity suitable for labeling with imaging or therapeutic radionuclides. We assess its versatile utility for serial tracking studies with PET and delivery of α-radionuclides to enhance anti-tumor killing efficacy in sub-optimal adoptive cell transfer in vivo using Thor-cells in lymphoma models. Results: We show that this reporter gene/probe platform enables repeated, sensitive, and specific assessment of the infused Thor-cells in the whole-body using PET/CT imaging with exceptionally high contrast. The uptake on PET correlates with the Thor-cells on a cellular and functional level. Furthermore, we report the ability of Thor-cells to accumulate cytotoxic alpha-emitting radionuclides preferentially at tumor sites, thus increasing therapeutic potency. Conclusion: Thor-cells are a new theranostic agent that may provide crucial information for better and safer clinical protocols of adoptive T cell therapies, as well as accelerated development strategies.

The risk index as a basis for risk/benefit analyses and protocol optimization in diagnostic nuclear imaging.

BACKGROUND: Potential risk associated with low-dose radiation exposures is often expressed using the effective dose (E) quantity. Other risk-related quantities have been proposed as alternatives. The recently introduced risk index (RI) shares similarities with E but expands the metric to incorporate medical imaging-appropriate risks factors including patient-specific size, age, and sex. PURPOSE: The aim of this work is to examine the RI metric for quantifying stochastic radiation risk and demonstrate its applications in nuclear imaging. The advantages in this improved metric may help the field progress toward stratified risk consideration in the course of patient management, improve efforts for procedure optimization, and support an evolution in the science of radiation risk assessment. METHODS: In this study we describe, implement, and calculate RI for various diagnostic nuclear imaging scenarios using reference biokinetics published in ICRP Publication 128 for commonly utilized radiopharmaceuticals. All absorbed dose, E and RI calculations were performed using the freely available MIRDcalc nuclear medicine dosimetry software; the organ specific risk parameters used in the software are also benchmarked in this text. The resulting RI and E values are compared and various trends in RI values identified. RESULTS: E and RI coefficients were calculated for 3016 use cases. Notably RI values vary depending on patient characteristics. Overall, across the population, global trends in RI values can be identified. In general, RI values were 2.15 times higher for females than males, due to higher risk coefficients and activities being distributed in smaller reference masses. The pediatric patients showed higher RIs than adults, as younger patients generally receive higher absorbed doses per administered activity, and are more radiosensitive, and have a longer projected lifespan at risk. A compendium of E and RI values is also provided in table format to serve as a reference for the community. CONCLUSIONS: RI is a rational quantity that could be used for justification, risk communication and protocol optimization in medical imaging. It has some advantages when compared to the long-utilized E value with respect to personalization, since accounts for patient size, age, sex, and natural incidence of cancer risk.

MIB Guides: Preclinical radiopharmaceutical dosimetry.

Preclinical dosimetry is essential for guiding the design of animal radiopharmaceutical biodistribution, imaging, and therapy experiments, evaluating efficacy and/or toxicities in such experiments, ensuring compliance with ethical standards for animal research, and providing reasonable initial estimates of normal-organ doses in humans, required for clinical translation of new radiopharmaceuticals. This MIB guide provides a basic protocol for obtaining preclinical dosimetry estimates with organ-level dosimetry software.

Simultaneous quantitative imaging of two PET radiotracers via the detection of positron-electron annihilation and prompt gamma emissions.

In conventional positron emission tomography (PET), only one radiotracer can be imaged at a time, because all PET isotopes produce the same two 511 keV annihilation photons. Here we describe an image reconstruction method for the simultaneous in vivo imaging of two PET tracers and thereby the independent quantification of two molecular signals. This method of multiplexed PET imaging leverages the 350-700 keV range to maximize the capture of 511 keV annihilation photons and prompt γ-ray emission in the same energy window, hence eliminating the need for energy discrimination during reconstruction or for signal separation beforehand. We used multiplexed PET to track, in mice with subcutaneous tumours, the biodistributions of intravenously injected [124I]I-trametinib and 2-deoxy-2-[18F]fluoro-D-glucose, [124I]I-trametinib and its nanoparticle carrier [89Zr]Zr-ferumoxytol, and the prostate-specific membrane antigen (PSMA) and infused PSMA-targeted chimaeric antigen receptor T cells after the systemic administration of [68Ga]Ga-PSMA-11 and [124I]I. Multiplexed PET provides more information depth, gives new uses to prompt γ-ray-emitting isotopes, reduces radiation burden by omitting the need for an additional computed-tomography scan and can be implemented on preclinical and clinical systems without any modifications in hardware or image acquisition software.

MIRD Pamphlet No. 28, Part 2: Comparative Evaluation of MIRDcalc Dosimetry Software Across a Compendium of Diagnostic Radiopharmaceuticals.

Radiopharmaceutical dosimetry is usually estimated via organ-level MIRD schema-style formalisms, which form the computational basis for commonly used clinical and research dosimetry software. Recently, MIRDcalc internal dosimetry software was developed to provide a freely available organ-level dosimetry solution that incorporates up-to-date models of human anatomy, addresses uncertainty in radiopharmaceutical biokinetics and patient organ masses, and offers a 1-screen user interface as well as quality assurance tools. The present work describes the validation of MIRDcalc and, secondarily, provides a compendium of radiopharmaceutical dose coefficients obtained with MIRDcalc. Biokinetic data for about 70 currently and historically used radiopharmaceuticals were obtained from the International Commission on Radiological Protection (ICRP) publication 128 radiopharmaceutical data compendium. Absorbed dose and effective dose coefficients were derived from the biokinetic datasets using MIRDcalc, IDAC-Dose, and OLINDA software. The dose coefficients obtained with MIRDcalc were systematically compared against the other software-derived dose coefficients and those originally presented in ICRP publication 128. Dose coefficients computed with MIRDcalc and IDAC-Dose showed excellent overall agreement. The dose coefficients derived from other software and the dose coefficients promulgated in ICRP publication 128 both were in reasonable agreement with the dose coefficients computed with MIRDcalc. Future work should expand the scope of the validation to include personalized dosimetry calculations.

MIRD Pamphlet No. 28, Part 1: MIRDcalc-A Software Tool for Medical Internal Radiation Dosimetry.

Medical internal radiation dosimetry constitutes a fundamental aspect of diagnosis, treatment, optimization, and safety in nuclear medicine. The MIRD committee of the Society of Nuclear Medicine and Medical Imaging developed a new computational tool to support organ-level and suborgan tissue dosimetry (MIRDcalc, version 1). Based on a standard Excel spreadsheet platform, MIRDcalc provides enhanced capabilities to facilitate radiopharmaceutical internal dosimetry. This new computational tool implements the well-established MIRD schema for internal dosimetry. The spreadsheet incorporates a significantly enhanced database comprising details for 333 radionuclides, 12 phantom reference models (International Commission on Radiological Protection), 81 source regions, and 48 target regions, along with the ability to interpolate between models for patient-specific dosimetry. The software also includes sphere models of various composition for tumor dosimetry. MIRDcalc offers several noteworthy features for organ-level dosimetry, including modeling of blood source regions and dynamic source regions defined by user input, integration of tumor tissues, error propagation, quality control checks, batch processing, and report-preparation capabilities. MIRDcalc implements an immediate, easy-to-use single-screen interface. The MIRDcalc software is available for free download (www.mirdsoft.org) and has been approved by the Society of Nuclear Medicine and Molecular Imaging.

Influence of Body Posture on Internal Organ Dosimetry: Radiocesium Exposure Modeling Using Novel Posture-dependent Mesh Computational Phantoms.

ABSTRACT: Current practice in reference internal dosimetry assumes a fixed upright standing posture is maintained throughout the dose-integration period. Recently, the mesh-type ICRP adult reference computational phantoms were transformed into different body postures (e.g., sitting, squatting) for use in occupational dose reconstruction applications. Here, for the first time, we apply this phantom series to the study of organ dose estimates following radionuclide intake. We consider the specific cases of 137 Cs and 134 Cs ingestion (accidental/occupational intake) with attention to variability in absorbed dose as a function of posture. The ICRP Publication 137 systemic biokinetic model for soluble cesium ingestion was used to compute organ-level time-integrated activity coefficients for reference adults, over a 50-y dose-integration period, for 134 Cs and 137 Cs (and its radioactive progeny 137m Ba). Mean posture time-allocations (h d -1 for standing, sitting, and lying) were taken from published survey data. In accord with modern dosimetry formalisms (e.g., MIRD, ICRP), a posture weighting factor was introduced that accounts for the fraction of time spent within each independent posture. Absorbed dose coefficients were computed using PHITS Monte Carlo simulations. ICRP 103 tissue weighting factors were applied along with the posture weighting factors to obtain committed effective dose per unit intake (Sv Bq -1 ). For 137 Cs ingestion, most organ absorbed dose coefficients were negligibly to marginally higher (< ~3%) for sitting or crouched (lying fetal/semi-fetal) postures maintained over the dose commitment period, relative to the upright standing posture. The committed effective dose coefficients were 1.3 × 10 -8 Sv Bq -1 137 Cs for standing, sitting, or crouched postures; thus, the posture-weighted committed effective dose was not significantly different than the committed effective dose for a maintained upright standing posture. For 134 Cs ingestion, most organ absorbed dose coefficients for the sitting and crouched postures were significantly larger than the standing posture, but the differences were still considered minor (< ~8% for most organs). The committed effective dose coefficients were 1.2 × 10 -8 Sv Bq -1 134 Cs for the standing posture and 1.3 × 10 -8 Sv Bq -1 134 Cs for the sitting or crouched posture. The posture-weighted committed effective dose was 1.3 × 10 -8 Sv Bq -1 134 Cs. Body posture has minor influence on organ-level absorbed dose coefficients and committed effective dose for ingestion of soluble 137 Cs or 134 Cs.

Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [177Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [177Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [177Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [177Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.

PET Imaging of Acidic Tumor Environment With 89Zr-labeled pHLIP Probes.

Acidosis of the tumor microenvironment is a hallmark of tumor progression and has emerged as an essential biomarker for cancer diagnosis, prognosis, and evaluation of treatment response. A tool for quantitatively visualizing the acidic tumor environment could significantly advance our understanding of the behavior of aggressive tumors, improving patient management and outcomes. 89Zr-labeled pH-low insertion peptides (pHLIP) are a class of radiopharmaceutical imaging probes for the in vivo analysis of acidic tumor microenvironments via positron emission tomography (PET). Their unique structure allows them to sense and target acidic cancer cells. In contrast to traditional molecular imaging agents, pHLIP's mechanism of action is pH-dependent and does not rely on the presence of tumor-specific molecular markers. In this study, one promising acidity-imaging PET probe ([89Zr]Zr-DFO-Cys-Var3) was identified as a candidate for clinical translation.

Delta-like ligand 3-targeted radioimmunotherapy for neuroendocrine prostate cancer.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer with limited meaningful treatment options. NEPC lesions uniquely express delta-like ligand 3 (DLL3) on their cell surface. Taking advantage of DLL3 overexpression, we developed and evaluated lutetium-177 (177Lu)-labeled DLL3-targeting antibody SC16 (177Lu-DTPA-SC16) as a treatment for NEPC. SC16 was functionalized with DTPA-CHX-A" chelator and radiolabeled with 177Lu to produce 177Lu-DTPA-SC16. Specificity and selectivity of 177Lu-DTPA-SC16 were evaluated in vitro and in vivo using NCI-H660 (NEPC, DLL3-positive) and DU145 (adenocarcinoma, DLL3-negative) cells and xenografts. Dose-dependent treatment efficacy and specificity of 177Lu-DTPA-SC16 radionuclide therapy were evaluated in H660 and DU145 xenograft-bearing mice. Safety of the agent was assessed by monitoring hematologic parameters. 177Lu-DTPA-SC16 showed high tumor uptake and specificity in H660 xenografts, with minimal uptake in DU145 xenografts. At all three tested doses of 177Lu-DTPA-SC16 (4.63, 9.25, and 27.75 MBq/mouse), complete responses were observed in H660-bearing mice; 9.25 and 27.75 MBq/mouse doses were curative. Even the lowest tested dose proved curative in five (63%) of eight mice, and recurring tumors could be successfully re-treated at the same dose to achieve complete responses. In DU145 xenografts, 177Lu-DTPA-SC16 therapy did not inhibit tumor growth. Platelets and hematocrit transiently dropped, reaching nadir at 2 to 3 wk. This was out of range only in the highest-dose cohort and quickly recovered to normal range by week 4. Weight loss was observed only in the highest-dose cohort. Therefore, our data demonstrate that 177Lu-DTPA-SC16 is a potent and safe radioimmunotherapeutic agent for testing in humans with NEPC.

Radioimmunotherapy Targeting Delta-like Ligand 3 in Small Cell Lung Cancer Exhibits Antitumor Efficacy with Low Toxicity.

PURPOSE: Small cell lung cancer (SCLC) is an exceptionally lethal form of lung cancer with limited treatment options. Delta-like ligand 3 (DLL3) is an attractive therapeutic target as surface expression is almost exclusive to tumor cells. EXPERIMENTAL DESIGN: We radiolabeled the anti-DLL3 mAb SC16 with the therapeutic radioisotope, Lutetium-177. [177Lu]Lu-DTPA-CHX-A"-SC16 binds to DLL3 on SCLC cells and delivers targeted radiotherapy while minimizing radiation to healthy tissue. RESULTS: [177Lu]Lu-DTPA-CHX-A"-SC16 demonstrated high tumor uptake with DLL3-target specificity in tumor xenografts. Dosimetry analyses of biodistribution studies suggested that the blood and liver were most at risk for toxicity from treatment with high doses of [177Lu]Lu-DTPA-CHX-A"-SC16. In the radioresistant NCI-H82 model, survival studies showed that 500 µCi and 750 µCi doses of [177Lu]Lu-DTPA-CHX-A"-SC16 led to prolonged survival over controls, and 3 of the 8 mice that received high doses of [177Lu]Lu-DTPA-CHX-A"-SC16 had pathologically confirmed complete responses (CR). In the patient-derived xenograft model Lu149, all doses of [177Lu]Lu-DTPA-CHX-A"-SC16 markedly prolonged survival. At the 250 µCi and 500 µCi doses, 5 of 10 and 7 of 9 mice demonstrated pathologically confirmed CRs, respectively. Four of 10 mice that received 750 µCi of [177Lu]Lu-DTPA-CHX-A"-SC16 demonstrated petechiae severe enough to warrant euthanasia, but the remaining 6 mice demonstrated pathologically confirmed CRs. IHC on residual tissues from partial responses confirmed retained DLL3 expression. Hematologic toxicity was dose-dependent and transient, with full recovery within 4 weeks. Hepatotoxicity was not observed. CONCLUSIONS: Together, the compelling antitumor efficacy, pathologic CRs, and mild and transient toxicity profile demonstrate strong potential for clinical translation of [177Lu]Lu-DTPA-CHX-A"-SC16.

Imaging of Cancer γ-Secretase Activity Using an Inhibitor-Based PET Probe.

PURPOSE: Abnormal Notch signaling promotes cancer cell growth and tumor progression in various cancers. Targeting γ-secretase, a pivotal regulator in the Notch pathway, has yielded numerous γ-secretase inhibitors (GSIs) for clinical investigation in the last 2 decades. However, GSIs have demonstrated minimal success in clinical trials in part due to the lack of specific and precise tools to assess γ-secretase activity and its inhibition in vivo. EXPERIMENTAL DESIGN: We designed an imaging probe based on GSI Semagacestat structure and synthesized the radioiodine-labeled analogues [131I]- or [124I]-PN67 from corresponding trimethyl-tin precursors. Both membrane- and cell-based ligand-binding assays were performed using [131I]-PN67 to determine the binding affinity and specificity for γ-secretase in vitro. Moreover, we evaluated [124I]-PN67 by PET imaging in mammary tumor and glioblastoma mouse models. RESULTS: The probe was synthesized through iodo-destannylation using chloramine-T as an oxidant with a high labeling yield and efficiency. In vitro binding results demonstrate the high specificity of this probe and its ability for target replacement study by clinical GSIs. PET imaging studies demonstrated a significant (P < 0.05) increased in the uptake of [124I]-PN67 in tumors versus blocking or sham control groups across multiple mouse models, including 4T1 allograft, MMTV-PyMT breast cancer, and U87 glioblastoma allograft. Ex vivo biodistribution and autoradiography corroborate these results, indicating γ-secretase specific tumor accumulation of [124I]-PN67. CONCLUSIONS: [124I]-PN67 is a novel PET imaging agent that enables assessment of γ-secretase activity and target engagement of clinical GSIs.

Patient Size-Dependent Dosimetry Methodology Applied to 18F-FDG Using New ICRP Mesh Phantoms.

Despite the known influence of anatomic variability on internal dosimetry, dosimetry for 18F-FDG and other diagnostic radiopharmaceuticals is routinely derived using reference phantoms, which embody population-averaged morphometry for a given age and sex. Moreover, phantom format affects dosimetry estimates to varying extent. Here, we applied newly developed mesh format reference phantoms and a patient-dependent phantom library to assess the impact of height, weight, and body contour variation on dosimetry of 18F-FDG. We compared the mesh reference phantom dosimetry estimates with corresponding estimates from common software to identify differences related to phantom format or software implementation. Our study serves as an example of how more precise patient size-dependent dosimetry methodology could be performed. Methods: Absorbed dose coefficients were computed for the adult mesh reference phantoms and derivative patient-dependent phantom series by Monte Carlo simulation using the PHITS radiation transport code within PARaDIM software. The dose coefficients were compared with reference absorbed dose coefficients obtained from ICRP Publication 128, or generated using software including OLINDA 2.1, OLINDA 1.1, and IDAC-dose 2.1. Results: Differences in dosimetry arising from anatomical variations were shown to be significant, with detriment-weighted dose coefficients for the percentile-specific phantoms varying by up to ±40% relative to the corresponding reference phantom effective dose coefficients, irrespective of phantom format. Similar variations were seen in the individual organ absorbed dose coefficients for the percentile-specific phantoms relative to the reference phantoms. The effective dose coefficient for the mesh reference adult was 0.017 mSv/MBq, which was 5% higher than estimated by a corresponding voxel phantom, and 10% lower than estimated by the stylized phantom format. Conclusion: We observed notable variability in 18F-FDG dosimetry across morphometrically different patients, supporting the use of patient-dependent phantoms for more accurate dosimetric estimations relative to standard reference dosimetry. These data may help in optimizing imaging protocols and research studies, in particular when longer-lived isotopes are employed.