Ultrasound-Assisted Solid-Phase Affibody Synthesis Using Z as an Example-Superior to the Conventional Protocol?

Background: Affibody molecules represent a class of highly specific binders of particular interest for the development of highly affine target-specific radiopharmaceuticals. Their chemical synthesis is, however, intricate due to their considerable length of 58 amino acids; thus, approaches to optimize their preparation are constantly being sought.

Methods: As ultrasound assistance has recently been shown to increase the efficiency of amino acid conjugation during solid-phase peptide synthesis (SPPS), the influence of ultrasonication on the outcome of the SPPS-based preparation of the EGFR-specific affibody Z was compared to a common protocol relying on mechanical shaking.

Lenticulostriatal Ischemia Shows Relevant SSTR Expression on PET/CT Imaging Using the Novel SSTR-Targeting Peptide 18 F-SiTATE.

A 64-year-old woman with meningioma presented with left-sided lenticulostriatal ischemia following craniotomy and debulking of a sphenoid wing meningioma. For subsequent radiotherapy planning, an SSTR-targeted PET/CT using the novel ligand 18 F-SiTATE was performed 2.5 months thereafter.

Suppressing Protodeboronation in Cu-Mediated F/F-Fluorination of Arylboronic Acids: A Mechanistically Guided Approach Towards Optimized PET Probe Development.

Fluorinated arenes play a crucial role in drug discovery, specialty materials, and medical imaging. Although several variants for Cu-mediated nucleophilic fluorination of arylboronic acids and derivatives have been developed, these protocols rarely address the occurrence and control of protodeboronation, which greatly complicates product separation and can compromise the effectiveness of a radiotracer for in vivo imaging. Consequently, simpler and more efficient procedures are needed to allow rapid F/F-fluorination of both arylboronic acids and esters while minimizing protodeboronation.

Type II & III inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update.

Introduction: The Trk family proteins are membrane-bound kinases predominantly expressed in neuronal tissues. Activated by neurotrophins, they regulate critical cellular processes through downstream signaling pathways. Dysregulation of Trk signaling can drive a range of diseases, making the design and study of Trk inhibitors a vital area of research.

PET Imaging in Dementia: Mini-Review and Canadian Perspective for Clinical Use.

PET imaging is increasingly recognized as an important diagnostic tool to investigate patients with cognitive disturbances of possible neurodegenerative origin. PET with 2-[F]fluoro-2-deoxy-D-glucose ([F]FDG), assessing glucose metabolism, provides a measure of neurodegeneration and allows a precise differential diagnosis among the most common neurodegenerative diseases, such as Alzheimer's disease, frontotemporal dementia or dementia with Lewy bodies. PET tracers specific for the pathological deposits characteristic of different neurodegenerative processes, namely amyloid and tau deposits typical of Alzheimer's Disease, allow the visualization of these aggregates .

Radiosynthesis of Stable Au-Nanoparticles by Neutron Activation of αβ-Specific AuNPs for Therapy of Tumor Angiogenesis.

This paper reports on the development of stable tumor-specific gold nanoparticles (AuNPs) activated by neutron irradiation as a therapeutic option for the treatment of cancer with high tumor angiogenesis. The AuNPs were designed with different mono- or dithiol-ligands and decorated with different amounts of Arg-Gly-Asp (RGD) peptides as a tumor-targeting vector for αβ integrin, which is overexpressed in tissues with high tumor angiogenesis. The AuNPs were evaluated for avidity in vitro and showed favorable properties with respect to tumor cell accumulation.

Silicon-Fluoride Acceptors (SiFA) for F-Radiolabeling: From Bench to Bedside.

Fluorine-18 (F) is undoubtedly one of the most frequently applied radionuclides for the development of new radiotracers for positron emission tomography (PET) in the context of clinical cancer, neurological, and metabolic imaging. Until recently, the available radiochemical methodologies to introduce F into organic molecules ranging from small- to medium- and large-sized compounds were limited to a few applicable protocols. With the advent of late-stage fluorination of small aromatic, nonactivated compounds and various noncanonical labeling strategies geared toward the labeling of peptides and proteins, the molecular toolbox for PET radiotracer development was substantially extended.

CycloSiFA: The Next Generation of Silicon-Based Fluoride Acceptors for Positron Emission Tomography (PET).

The ring-opening Si-fluorination of a variety of azasilole derivatives cyclo-1-(iPr Si)-4-X-C H -2-CH NR (4: R=2,6-iPr C H , X=H; 4 a: R=2,4,6-Me C H , X=H; 9: R=2,6-iPr C H , X=tBuMe SiO; 10: R=2,6-iPr C H , X=OH; 13: R=2,6-iPr C H , X=HCCCH O; 22: R=2,6-iPr C H , X=tBuMe SiCH O) with different F-fluoride sources was studied, optimized and the experience gained was used in a translational approach to create a straightforward F-labelling protocol for the azasilole derivatives [ F]6 and [ F]14. The latter constitutes a potential clickable CycloSiFA prosthetic group which might be used in PET tracer development using Cu-catalysed triazole formation. Based on our findings, CycloSiFA has the potential to become a new entry into non-canonical labelling methodologies for radioactive PET tracer development.

Good practices for the automated production of F-SiFA radiopharmaceuticals.

Background: The positron emitting isotope fluorine-18 (F) possesses almost ideal physicochemical properties for the development of radiotracers for diagnostic molecular imaging employing positron emission tomography (PET). F in its nucleophilic anionic F form is usually prepared by bombarding an enriched O water target with protons of various energies between 5 and 20 MeV depending on the technical specifications of the cyclotron. Large thick-target yields between 5 and 14 GBq/µA can be obtained, enough to prepare large batches of radiotracers capable to serve a considerable contingent of patients (50 + per clinical batch).

Type I inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update.

Introduction: Trk inhibitors are significant in the realm of personalized medicine as they target specific genetic alterations, such as gene fusions, leading to improved treatment outcomes for cancer patients. By tailoring the treatment to the genetic characteristics of the tumor rather than the tumor type, Trk inhibitors offer the potential for more effective and precise therapies, resulting in enhanced response rates and prolonged survival for patients with fusion-positive cancers.

Areas Covered: Patents covering type I inhibitors targeting the Trk family are discussed, building upon our prior review series on Trk inhibitors.

Next-generation PET/CT imaging in meningioma-first clinical experiences using the novel SSTR-targeting peptide [F]SiTATE.

Background: Somatostatin-receptor (SSTR)-targeted PET/CT provides important clinical information in addition to standard imaging in meningioma patients. [F]SiTATE is a novel, F-labeled SSTR-targeting peptide with superior imaging properties according to preliminary data. We provide the first [F]SiTATE PET/CT data of a large cohort of meningioma patients.

Towards Radiolabeled EGFR-Specific Peptides: Alternatives to GE11.

The human epidermal growth factor receptor (EGFR) is closely related to several cancer-promoting processes and overexpressed on a variety of tumor types, rendering it an important target structure for the imaging and therapy of several malignancies. To date, approaches to develop peptidic radioligands able to specifically address and visualize EGFR-positive tumors have been of limited success. Most of the attempts were based on the lead GE11, as this peptide was previously described to be a highly potent EGFR-specific agent.

Comparison of somatostatin receptor expression in patients with neuroendocrine tumours with and without somatostatin analogue treatment imaged with [F]SiTATE.

Purpose: Somatostatin analogues (SSA) are frequently used in the treatment of neuroendocrine tumours. Recently, [F]SiTATE entered the field of somatostatin receptor (SSR) positron emission tomography (PET)/computed tomography (CT) imaging. The purpose of this study was to compare the SSR-expression of differentiated gastroentero-pancreatic neuroendocrine tumours (GEP-NET) measured by [18F]SiTATE-PET/CT in patients with and without previous treatment with long-acting SSAs to evaluate if SSA treatment needs to be paused prior to [18F]SiTATE-PET/CT.

Synthesis, Radiolabeling, and and Characterization of Heterobivalent Peptidic Agents for Bispecific EGFR and Integrin αβ Targeting.

Radiolabeled heterobivalent peptidic ligands (HBPLs) are a highly promising compound class for the sensitive and specific visualization of tumors as they often exhibit superior properties compared to their monospecific counterparts and are able to concomitantly or complementarily address different receptor types. The combination of two receptor-specific agents targeting the epidermal growth factor receptor (EGFR) and the integrin αβ in one HBPL would constitute a synergistic combination of binding motifs as these two receptor types are concurrently overexpressed on several human tumor types and are closely associated with disease progression and metastasis. Here, we designed and synthesized two heterobivalent radioligands consisting of the EGFR-specific peptide GE11 and αβ-specific cyclic RGD peptides, bearing a (1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid chelator for efficient radiolabeling and linkers of different lengths between both peptides.

Toward Optimized Zr-Immuno-PET: Side-by-Side Comparison of [Zr]Zr-DFO-, [Zr]Zr-3,4,3-(LI-1,2-HOPO)- and [Zr]Zr-DFO*-Cetuximab for Tumor Imaging: Which Chelator Is the Most Suitable?

89Zr represents a highly favorable positron emitter for application in immuno-PET (Positron Emission Tomography) imaging. Clinically, the 89Zr4+ ion is introduced into antibodies by complexation with desferrioxamine B. However, producing complexes of limited kinetic inertness.

Synthesis of a Bifunctional Cross-Bridged Chelating Agent, Peptide Conjugation, and Comparison of Ga Labeling and Complex Stability Characteristics with Established Chelators.

[ Ga]Ga can be introduced into receptor-specific peptidic carriers via different chelators to obtain radiotracers for Positron Emission Tomography imaging and the chosen chelating agent considerably influences the in vivo pharmacokinetics of the corresponding radiopeptides. A chelator that should be a valuable alternative to established chelating agents for Ga-radiolabeling of peptides would be a backbone-functionalized variant of the chelator CB-DO2A. Here, the bifunctional cross-bridged chelating agent CB-DO2A-GA was developed and compared to the established chelators DOTA, NODA-GA and DOTA-GA.

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.

Simultaneous PET/MRI: The future gold standard for characterizing motor neuron disease-A clinico-radiological and neuroscientific perspective.

Neuroimaging assessment of motor neuron disease has turned into a cornerstone of its clinical workup. Amyotrophic lateral sclerosis (ALS), as a paradigmatic motor neuron disease, has been extensively studied by advanced neuroimaging methods, including molecular imaging by MRI and PET, furthering finer and more specific details of the cascade of ALS neurodegeneration and symptoms, facilitated by multicentric studies implementing novel methodologies. With an increase in multimodal neuroimaging data on ALS and an exponential improvement in neuroimaging technology, the need for harmonization of protocols and integration of their respective findings into a consistent model becomes mandatory.

Toward the Development of GE11-Based Radioligands for Imaging of Epidermal Growth Factor Receptor-Positive Tumors.

The epidermal growth factor receptor (EGFR) is closely associated with tumor development and progression and thus an important target structure for imaging and therapy of various tumors. As a result of its important role in malignancies of various origins and the fact that antibody-based compounds targeting the EGFR have significant drawbacks in terms of pharmacokinetics, several attempts have been made within the last five years to develop peptide-based EGFR-specific radioligands based on the GE11 scaffold. However, none of these approaches have shown convincing results so far, which has been proposed to be attributed to different potential challenges associated with the GE11 lead structure: first, an aggregation of radiolabeled peptides, which might prevent their interaction with their target receptor, or second, a relatively low affinity of monomeric GE11, necessitating its conversion into a multimeric or polymeric form to achieve adequate EGFR-targeting properties.

Toward in vivo proof of binding of F-labeled inhibitor [F]TRACK to peripheral tropomyosin receptor kinases.

Background: Tropomyosin receptor kinases (TrkA, TrkB, TrkC) are a family of tyrosine kinases primarily expressed in neuronal cells of the brain. Identification of oncogenic alterations in Trk expression as a driver in multiple tumor types has increased interest in their role in human cancers. Recently, first- and second-generation C and F-labeled Trk inhibitors, e.