Chang-Tong Yang

Background: Metabotropic glutamate receptor subtype 5 (mGluR5) is a promising therapeutic target for a range of neuropsychiatric disorders, and [¹⁸F]FPEB is a PET radioligand developed for imaging central mGluR5 receptor availability. This study aimed to determine the biodistribution, kinetic characteristics, and radiation dosimetry of [¹⁸F]FPEB in healthy Asian subjects and to evaluate the feasibility of reference tissue models as alternatives to conventional blood-based kinetic modeling. Methods: Five healthy Asian male volunteers underwent whole-body and dynamic brain PET imaging following administration of [¹⁸F]FPEB. Radiation dosimetry was estimated using OLINDA/EXM software. Tracer kinetics were analyzed using both blood-based compartmental models and reference tissue models to derive regional binding potentials (BPND) and volumes of distribution. Model performance was assessed using the Akaike Information Criterion (AIC). Results: The mean whole-body effective radiation dose was 0.703 mSv/mCi, with the gallbladder identified as the critical organ receiving the highest absorbed dose (5.63 mGy/mCi). Brain time–activity curves demonstrated the highest tracer uptake in the nucleus accumbens, followed by the cingulate gyrus, putamen, and insula, with moderate uptake in the thalamus and globus pallidus and the lowest uptake in the brainstem and cerebellum. Using the simplified reference tissue models (SRTM/SRTM2), the highest BPND values were observed in the nucleus accumbens, followed by the cingulate gyrus, putamen, and insula. In contrast, two-tissue compartment models (2TCM/2TCM-C) showed the highest BPND values in the hippocampus, followed by the amygdala, nucleus accumbens, and caudate nucleus. Although differences were observed in the absolute BPND values and regional ranking, both modeling approaches identified similar brain regions with high mGluR5 binding. Conclusions: [¹⁸F]FPEB demonstrated a favorable radiation dosimetry profile and supports the feasibility of reference tissue models for BPND estimation in healthy Asian subjects. These findings provide preliminary baseline data, although validation in larger cohorts is needed to confirm the pharmacokinetic characteristics and modeling approach.

Address for correspondence: Chang-Tong Yang, Radiological Sciences Division, Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Block 2, Basement 1, Outram Road, Singapore 169608, Singapore (e-mail: yang.changtong@sgh.com.sg). Abstract Objectives: High-risk childhood neuroblastoma patients have poor survival outcomes with few treatment options for relapse or refractory disease. Targeted immunotherapy using a monoclonal antibody against a tumor-associated antigen, the disialoganglioside GD2, is increasingly used, but the treatment has side effects and is costly. Development of a noninvasive tool to image and quantify the presence of the GD2 tumor antigen may help in patient selection. The aim of this study is to label anti-GD2 antibody APN311 with radioactive iodine (I-131 and I-124), analyze the biodistribution, and perform PET imaging in neuroblastoma xenograft tumor–bearing mice. Methods: APN311, a monoclonal chimeric antibody targeting the GD2 antigen, was labeled with radioactive iodine using the chloramine-T approach. Biodistribution studies were performed at 6, 24, 48, and 72 hours postinjection of 0.8 to 1.2 Mbq ¹³¹I-APN311 into BALB/c mice bearing high and low GD2-expressing patient-derived neuroblastoma xenografts. MicroPET images were acquired 48 and 72 hours after injection of 10 MBq of ¹²⁴I-APN311. All experiments were done in compliance with, and with the approval of, the Institutional Animal Care and Use Committee. Results: APN311 was radiolabeled with ¹³¹I successfully with high efficiency and isolated in high purity (>98%). Biodistribution studies showed a high tumor-to-normal tissue ratio, with tumor-to-blood ratios of 3.9:1 at 48 hours and 9.1:1 at 72 hours. MicroPET imaging further confirmed preferential uptake of ¹²⁴I-APN311 in high GD2-expressing tumors compared with low GD2-expressing tumors, with uptake values of 11.4 versus 3.2% ID/g at 48 hours, and 5.6 versus 1.2% ID/g at 72 hours, respectively. These findings indicate the selective targeting capability of ¹²⁴I-APN311 for high GD2-expressing tumors. Conclusion: In our preclinical model, both ¹³¹I and ¹²⁴I-APN311 displayed high tumor-to-normal tissue contrast for the detection of GD2 tumor antigen in patient-derived neuroblastoma xenografts. Our study strongly supports the potential clinical utility of radio-iodine-labeled APN311 in assessing GD2 expression status in neuroblastoma tumors. Article published online: 06 January 2026 © 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India

The proper functioning of mitochondria requires preserving the membrane potential (ΔΨm) within a narrow window. Significant deviation from the membrane potential of mitochondria is a well-established indicator of mitochondrial dysfunction. Various pathological conditions, such as cancer, diabetes, and cardiotoxicity, have been linked to mitochondrial dysfunction, highlighting the need for reliable methods to assess membrane potential in vivo. Hence, there is a need to explore radiolabeled lipophilic cations that accumulate within mitochondria in proportion to the potential gradient. The lipophilic organic cation triphenylphosphonium (TPP) has gained attention as a promising tracer for non-invasive imaging of mitochondrial function. It has been labeled with various radioisotopes, such as F-18, for imaging mitochondrial membrane potential in cancer through positron emission tomography (PET). The first attempt to quantify membrane potential in living organisms by examining the biodistribution of the 11C-labeled TPP derivative was reported more than 30 years ago. Herein, a series of TPP derivatives, together with TPP, have been radiolabeled with 64Cu for imaging gliomas, which are characterized by high mitochondrial content. 2-(diphenylphosphoryl)-ethyldiphenylphosphonium (TPEP) has demonstrated superior tumor uptake and favorable tumor-to-background ratios, leading to its selection for further assessment as a magnetic resonance imaging contrast agent. Building on these findings, we developed 68Ga-labeled TPP and TPEP as novel PET tracers for rhabdomyosarcoma. To assess how the choice of targeting moiety and bifunctional chelator influences tracer performance, biodistribution studies were conducted in mitochondrial-rich rhabdomyosarcoma patient-derived xenografts. These results support further development of 68Ga-TPP-based agents for mitochondrial-targeted oncologic imaging applications.

Mesenchymal stem/stromal cells (MSCs) are an extensively studied cell type in clinical trials due to their easy availability, substantial ex vivo proliferative capacity, and therapeutic efficacy in numerous pre-clinical animal models of disease. The prevailing understanding suggests that their therapeutic impact is mediated by the secretion of exosomes. Notably, MSC exosomes present several advantages over MSCs as therapeutic agents, due to their non-living nature and smaller size. However, despite their promising therapeutic potential, the clinical translation of MSC exosomes is hindered by an incomplete understanding of their biodistribution after administration. A primary obstacle to this lies in the lack of robust labels that are highly sensitive, capable of directly and easily tagging exosomes with minimal non-specific labeling artifacts, and sensitive traceability with minimal background noise. One potential candidate to address this issue is radioactive iodine. Protocols for iodinating exosomes and tracking radioactive iodine in live imaging are well-established, and their application in determining the biodistribution of exosomes has been reported. Nevertheless, the effects of iodination on the structural or functional activities of exosomes have never been thoroughly examined. In this study, we investigate these effects and report that these iodination methods abrogate CD73 enzymatic activity on MSC exosomes. Consequently, the biodistribution of iodinated exosomes may reflect the biodistribution of denatured exosomes rather than functionally intact ones.

Quantitative nuclear imaging techniques are in high demand for various disease diagnostics and cancer theranostics. The non-invasive imaging modality requires radiotracing through the radioactive decay emission of the radionuclide. Current preclinical and clinical radiotracers, so-called nuclear imaging probes, are radioisotope-labeled small molecules. Liposomal radiotracers have been rapidly developing as novel nuclear imaging probes. The physicochemical properties and structural characteristics of liposomes have been elucidated to address their long circulation and stability as radiopharmaceuticals. Various radiolabeling methods for synthesizing radionuclides onto liposomes and synthesis strategies have been summarized to render them biocompatible and enable specific targeting. Through a variety of radionuclide labeling methods, radiolabeled liposomes for use as nuclear imaging probes can be obtained for in vivo biodistribution and specific targeting studies. The advantages of radiolabeled liposomes including their use as potential clinical nuclear imaging probes have been highlighted. This review is a comprehensive overview of all recently published liposomal SPECT and PET imaging probes.

Yttrium-90 (⁹⁰Y) microspheres are widely used for the treatment of liver-dominant malignant tumors. They are infused via catheter into the hepatic artery branches supplying the tumor under fluoroscopic guidance based on pre-therapy angiography and Technetium-99m macroaggregated albumin (^99mTc-MAA) planning. However, at present, these microspheres are suspended in radiolucent media such as dextrose 5% (D5) solution. In order to monitor the real-time implantation of the microspheres into the tumor, the ⁹⁰Y microspheres could be suspended in omnipaque contrast for allowing visualization of the correct distribution of the microspheres into the tumor. The radiochemical purity of mixing ⁹⁰Y-microspheres in various concentrations of omnipaque was investigated. The radiochemical purity and feasibility of mixing ^99mTc-MAA with various concentrations of a standard contrast agent were also investigated. Results showed the radiochemical feasibility of mixing ⁹⁰Y-microspheres with omnipaque is radiochemically acceptable for allowing real-time visualization of radioembolization under fluoroscopy.

Nuclear imaging is a powerful non-invasive imaging technique that is rapidly developing in medical theranostics. Nuclear imaging requires radiolabeling isotopes for non-invasive imaging through the radioactive decay emission of the radionuclide. Nuclear imaging probes, commonly known as radiotracers, are radioisotope-labeled small molecules. Nanomaterials have shown potential as nuclear imaging probes for theranostic applications. By modifying the surface of nanomaterials, multifunctional radio-labeled nanomaterials can be obtained for in vivo biodistribution and targeting in initial animal imaging studies. Various surface modification strategies have been developed, and targeting moieties have been attached to the nanomaterials to render biocompatibility and enable specific targeting. Through integration of complementary imaging probes to a single nanoparticulate, multimodal molecular imaging can be performed as images with high sensitivity, resolution, and specificity. In this review, nanomaterial nuclear imaging probes including inorganic nanomaterials such as quantum dots (QDs), organic nanomaterials such as liposomes, and exosomes are summarized. These new developments in nanomaterials are expected to introduce a paradigm shift in nuclear imaging, thereby creating new opportunities for theranostic medical imaging tools.

Traumatic brain injury (TBI) modelled by lateral fluid percussion-induction (LFPI) in rats is a widely used experimental rodent model to explore and understand the underlying cellular and molecular alterations in the brain caused by TBI in humans. Current improvements in imaging with positron emission tomography (PET) have made it possible to map certain features of TBI-induced cellular and molecular changes equally in humans and animals. The PET imaging technique is an apt supplement to nanotheranostic-based treatment alternatives that are emerging to tackle TBI. The present study aims to investigate whether the two radioligands, [¹¹C]PBR28 and [¹⁸F]flumazenil, are able to accurately quantify in vivo molecular-cellular changes in a rodent TBI-model for two different biochemical targets of the processes. In addition, it serves to observe any palpable variations associated with primary and secondary injury sites, and in the affected versus the contralateral hemispheres. As [¹¹C]PBR28 is a radioligand of the 18 kD translocator protein, the up-regulation of which is coupled to the level of neuroinflammation in the brain, and [¹⁸F]flumazenil is a radioligand for GABA_A-benzodiazepine receptors, whose level mirrors interneuronal activity and eventually cell death, the use of the two radioligands may reveal two critical features of TBI. An up-regulation in the [¹¹C]PBR28 uptake triggered by the LFP in the injured (right) hemisphere was noted on day 14, while the uptake of [¹⁸F]flumazenil was down-regulated on day 14. When comparing the left (contralateral) and right (LFPI) hemispheres, the differences between the two in neuroinflammation were obvious. Our results demonstrate a potential way to measure the molecular alterations in a rodent-based TBI model using PET imaging with [¹¹C]PBR28 and [¹⁸F]flumazenil. These radioligands are promising options that can be eventually used in exploring the complex in vivo pharmacokinetics and delivery mechanisms of nanoparticles in TBI treatment.