A Novel Luciferase-Based Reporter Gene Technology for Simultaneous Optical and Radionuclide Imaging of Cells.

Multimodality reporter gene imaging combines the sensitivity, resolution and translational potential of two or more signals. The approach has not been widely adopted by the animal imaging community, mainly because its utility in this area is unproven. We developed a new complementation-based reporter gene system where the large component of split NanoLuc luciferase (LgBiT) presented on the surface of cells (TM-LgBiT) interacts with a radiotracer consisting of the high-affinity complementary HiBiT peptide labeled with a radionuclide.

In vitro and in vivo analyses of eFAP: a novel FAP-targeting small molecule for radionuclide theranostics and other oncological interventions.

Background: Fibroblast activation protein (FAP), a transmembrane serine protease overexpressed by cancer-associated fibroblasts in the tumor stroma, is an interesting biomarker for targeted radionuclide theranostics. FAP-targeting radiotracers have demonstrated to be superior to [F]FDG PET/CT in various solid cancers. However, these radiotracers have suboptimal tumor retention for targeted radionuclide therapy (TRT).

eTFC-01: a dual-labeled chelate-bridged tracer for SSTR2-positive tumors.

Background: Integrating radioactive and optical imaging techniques can facilitate the prognosis and surgical guidance for cancer patients. Using a single dual-labeled tracer ensures consistency in both imaging modalities. However, developing such molecule is challenging due to the need to preserve the biochemical properties of the tracer while introducing bulky labeling moieties.

Synthesis and Evaluation of ePSMA-DM1: A New Theranostic Small-Molecule Drug Conjugate (T-SMDC) for Prostate Cancer.

Small-molecule drug conjugates (SMDCs) are compounds in which a therapeutic payload is conjugated to a targeting vector, for specific delivery to the tumor site. This promising approach can be translated to the treatment of prostate cancer by selecting a targeting vector which binds to the prostate-specific membrane antigen (PSMA). Moreover, the addition of a bifunctional chelator to the molecule allows for the use of both diagnostic and therapeutic radionuclides.

Side-by-side comparison of the two widely studied GRPR radiotracers, radiolabeled NeoB and RM2, in a preclinical setting.

Introduction: NeoB and RM2 are the most investigated gastrin-releasing peptide receptor (GRPR)-targeting radiotracers in preclinical and clinical studies. Therefore, an extensive side-by-side comparison of the two radiotracers is valuable to demonstrate whether one has advantages over the other. Accordingly, this study aims to compare the in vitro and in vivo characteristics of radiolabeled NeoB and RM2 to guide future clinical studies.

[Pb]Pb-eSOMA-01: A Promising Radioligand for Targeted Alpha Therapy of Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) has been applied to the treatment of neuroendocrine tumors (NETs) for over two decades. However, improvement is still needed, and targeted alpha therapy (TAT) with alpha emitters such as lead-212 (Pb) represents a promising avenue. A series of ligands based on octreotate was developed.

First preclinical evaluation of [Ac]Ac-DOTA-JR11 and comparison with [Lu]Lu-DOTA-JR11, alpha versus beta radionuclide therapy of NETs.

Background: The [Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters.

Radiochemical and Biological Evaluation of 3p--NETA-ePSMA-16, a Promising PSMA-Targeting Agent for Radiotheranostics.

Bifunctional chelators (BFCs) are a key element in the design of radiopharmaceuticals. By selecting a BFC that efficiently complexes diagnostic and therapeutic radionuclides, a theranostic pair possessing almost similar biodistribution and pharmacokinetic properties can be developed. We have previously reported 3p--NETA as a promising theranostic BFC, and the encouraging preclinical outcomes obtained with [F]AlF-3p--NETA-TATE led us to conjugate this chelator to a PSMA-targeting vector for imaging and treatment of prostate cancer.

Preclinical Evaluation of a PSMA-Targeting Homodimer with an Optimized Linker for Imaging of Prostate Cancer.

Prostate-specific membrane antigen (PSMA) targeting radiopharmaceuticals have been successfully used for diagnosis and therapy of prostate cancer. Optimization of the available agents is desirable to improve tumor uptake and reduce side effects to non-target organs. This can be achieved, for instance, via linker modifications or multimerization approaches.

Pre- and Intraoperative Visualization of GRPR-Expressing Solid Tumors: Preclinical Profiling of Novel Dual-Modality Probes for Nuclear and Fluorescence Imaging.

Image-guided surgery using a gastrin-releasing peptide receptor (GRPR)-targeting dual-modality probe could improve the accuracy of the resection of various solid tumors. The aim of this study was to further characterize our four previously developed GRPR-targeting dual-modality probes that vary in linker structures and were labeled with indium-111 and sulfo-cyanine 5. Cell uptake studies with GRPR-positive PC-3 cells and GRPR-negative NCI-H69 cells confirmed receptor specificity.

Direct comparison of [F]AlF-NOTA-JR11 and [F]AlF-NOTA-octreotide for PET imaging of neuroendocrine tumors: Antagonist versus agonist.

Background: [F]AlF-NOTA-octreotide is an F-labeled somatostatin analogue which is a good clinical alternative for Ga-labeled somatostatin analogues. However, radiolabeled somatostatin receptor (SSTR) antagonists might outperform agonists regarding imaging sensitivity of neuroendocrine tumors (NETs). No direct comparison between the antagonist [F]AlF-NOTA-JR11 and the agonist [F]AlF-NOTA-octreotide as SSTR PET probes is available.

Synthesis and radiolabelling of PSMA-targeted derivatives containing GYK/MVK cleavable linkers.

Targeted radionuclide therapy (TRT) is a promising strategy to treat different types of cancer. TRT relies on a targeting vector used to deliver a therapeutic radionuclide specifically to the tumour site. Several low molecular weight ligands targeting the prostate-specific membrane antigen (PSMA) have been synthesized, but their pharmacokinetic properties still need to be optimized.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biannual highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Main Body: This commentary of highlights has resulted in 21 different topics selected by each coauthoring Editorial Board member addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals.

Conclusion: Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field in various topics including new PET-labelling methods, FAPI-tracers and imaging, and radionuclide therapy being the scope of EJNMMI Radiopharmacy and Chemistry.

Synthesis and Evaluation of Two Long-Acting SSTR2 Antagonists for Radionuclide Therapy of Neuroendocrine Tumors.

Somatostatin receptor subtype 2 (SSTR2) has become an essential target for radionuclide therapy of neuroendocrine tumors (NETs). JR11 was introduced as a promising antagonist peptide to target SSTR2. However, due to its rapid blood clearance, a better pharmacokinetic profile is necessary for more effective treatment.

3p-C-NETA: A versatile and effective chelator for development of AlF-labeled and therapeutic radiopharmaceuticals.

: Radiolabeled somatostatin analogues ( [Ga]Ga-DOTATATE and [Lu]Lu-DOTATATE) have been used to diagnose, monitor, and treat neuroendocrine tumour (NET) patients with great success. [F]AlF-NOTA-octreotide, a promising F-labeled somatostatin analogue and potential alternative for Ga-DOTA-peptides, is under clinical evaluation. However, ideally, the same precursor (combination of chelator-linker-vector) can be used for production of both diagnostic and therapeutic radiopharmaceuticals with very similar ( AlF-method in combination with therapeutic radiometals Bi/Lu) or identical ( complementary Tb-radionuclides) pharmacokinetic properties, allowing for accurate personalised dosimetry estimation and radionuclide therapy of NET patients.

New Developments in Carbonic Anhydrase IX-Targeted Fluorescence and Nuclear Imaging Agents.

Carbonic anhydrase IX (CAIX) is a tumor-specific and hypoxia-induced biomarker for the molecular imaging of solid malignancies. The nuclear- and optical-imaging of CAIX-expressing tumors have received great attention due to their potential for clinical applications. Nuclear imaging is a powerful tool for the non-invasive diagnosis of primary and metastatic CAIX-positive tumors and for the assessment of responses to antineoplastic treatment.

Towards Complete Tumor Resection: Novel Dual-Modality Probes for Improved Image-Guided Surgery of GRPR-Expressing Prostate Cancer.

Nuclear and optical dual-modality probes can be of great assistance in prostate cancer localization, providing the means for both preoperative nuclear imaging and intraoperative surgical guidance. We developed a series of probes based on the backbone of the established GRPR-targeting radiotracer NeoB. The inverse electron demand of the Diels-Alder reaction was used to integrate the sulfo-cyanine 5 dye.

Tumor Microenvironment Responsive "Head-to-Foot" Self-Assembly Nanoplatform for Positron Emission Tomography Imaging in Living Subjects.

Sensitivity and specificity of molecular probes are two important factors in determining the accuracy of cancer diagnosis or the efficacy of cancer treatment. However, the development of probes with high sensitivity and strong specificity still poses many challenges. Herein, we report an F-labeled smart tracer ([F]) targeting cancer-associated biotin receptor (BR) and self-assembling into nanoparticles in response to intracellular glutathione.

EANM guideline for harmonisation on molar activity or specific activity of radiopharmaceuticals: impact on safety and imaging quality.

This guideline on molar activity (A) and specific activity (A) focusses on small molecules, peptides and macromolecules radiolabelled for diagnostic and therapeutic applications. In this guideline we describe the definition of A and A, and how these measurements must be standardised and harmonised. Selected examples highlighting the importance of A and A in imaging studies of saturable binding sites will be given, and the necessity of using appropriate materials and equipment will be discussed.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Results: This commentary of highlights has resulted in 21 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Also the first contribution in relation to MRI-agents is included.

IEDDA: An Attractive Bioorthogonal Reaction for Biomedical Applications.

The pretargeting strategy has recently emerged in order to overcome the limitations of direct targeting, mainly in the field of radioimmunotherapy (RIT). This strategy is directly dependent on chemical reactions, namely bioorthogonal reactions, which have been developed for their ability to occur under physiological conditions. The Staudinger ligation, the copper catalyzed azide-alkyne cycloaddition (CuAAC) and the strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) were the first bioorthogonal reactions introduced in the literature.