Drug delivery strategies to cross the blood-brain barrier in Alzheimer's disease: a comprehensive review on three promising strategies.

The field of Alzheimer's disease (AD) drug development is rapidly changing, with two anti-amyloid monoclonal antibodies (mAbs) having received Food and Drug Administration (FDA) approval, additionally many compounds are in the pipeline. A major obstacle for novel AD therapeutics is the blood-brain barrier (BBB), which restricts passage of particles larger than 400-500 Da. It is estimated that only ∼0.

Triflyl [F]Fluoride as a Solution for Base-Sensitive Late-Stage Nucleophilic Aromatic F-Fluorination Reactions.

Fluorine-18 is the predominant radionuclide used to label Positron Emission Tomography (PET) tracers. One outstanding challenge in nucleophilic aromatic radiofluorination reactions is the sensitivity of precursors and catalysts for basic reaction conditions, which are necessary for the work-up of [F]fluoride, resulting in limited reproducibility. Triflyl [F]fluoride is a new [F]fluoride source that allows freedom in choice of type and amounts of base and cryptand.

[F]Trifluoroiodomethane - Enabling Photoredox-mediated Radical [F]Trifluoromethylation for Positron Emission Tomography.

The development of new tracers for positron emission tomography (PET) is highly dependent on the available synthetic tools for their radiosynthesis. Herein, we present the radiosynthesis and application of [F]trifluoroiodomethane - the first reagent for broad scope radical [F]trifluoromethylation chemistry in high molar activity. CF FI can be prepared from [F]fluoroform with 67±5 % AY and >99 % RCP.

Whole-Body HER2 Heterogeneity Identified on HER2 PET in HER2-Negative, -Low, and -Positive Metastatic Breast Cancer.

Understanding which patients with human epidermal growth factor receptor 2 (HER2)-negative or -low metastatic breast cancer (MBC) benefit from HER2-targeted strategies is urgently needed. We assessed the whole-body heterogeneity of HER2 expression on Zr-trastuzumab PET (HER2 PET) and the diagnostic performance of HER2 PET in a large series of patients, including HER2-negative and -low MBC. In the IMPACT-MBC study, patients with newly diagnosed and nonrapidly progressive MBC of all subtypes were included.

Investigation of the Impact of the H310A FcRn Region Mutation on Zr-Immuno-PET Brain Imaging with a BBB-Shuttle Anti‑Amyloid Beta Antibody.

Purpose: In the emerging field of antibody treatments for neurodegenerative diseases, reliable tools are needed to evaluate new therapeutics, diagnose and select patients, monitor disease progression, and assess therapy response. Immuno-PET combines the high affinity and exceptional specificity of monoclonal antibodies with the non-invasive imaging technique positron emission tomography (PET). Its application in neurodegenerative disease brain imaging has been limited due to the marginal uptake across the blood-brain barrier (BBB).

Synthesis of F-labelled aryl trifluoromethyl ketones with improved molar activity.

A method for the radiosynthesis of F-labelled aryl trifluoromethyl ketones starting from widely available Weinreb amides using [F]fluoroform is presented. The method uses potassium hexamethyldisilazane as base and delivers products in high molar activity (up to 24 GBq μmol) and excellent radiochemical conversions. The applicability for PET tracer synthesis is demonstrated by the radiosynthesis of ten (hetero)aryl trifluoromethylketones, bearing electron-withdrawing and -donating substituents including a derivative of bioactive probenecid.

Improving Routine Zr-Immuno-PET Applications: Mild Iron Removal Can Favor the Use of Fe-DFO-N-suc-TFP Ester Over p-NCS-Bz-DFO.

A key aspect for the applicability of Zr-radioimmunoconjugates is inert modification and radiolabeling. The two commercially available bifunctional variants of the siderophore desferrioxamine (DFO), Fe-DFO-N-suc-TFP-ester and p-NCS-Bz-DFO, are most often used for clinical Zr-immuno-PET. The use of Fe-DFO-N-suc-TFP-ester is advantageous with regard to higher radiolysis stability and more facile assessment of radiochemical purity as well as chelator-to-mAb ratio.

Good practices for Zr radiopharmaceutical production and quality control.

Background: During the previous two decades, PET imaging of biopharmaceuticals radiolabeled with zirconium-89 has become a consistent tool in preclinical and clinical drug development and patient selection, primarily due to its advantageous physical properties that allow straightforward radiolabeling of antibodies (Zr-immuno-PET). The extended half-life of 78.4 h permits flexibility with respect to the logistics of tracer production, transportation, and imaging and allows imaging at later points in time.

Synthesis of F-labeled Aryl Trifluoromethyl Sulfones, -Sulfoxides, and -Sulfides for Positron Emission Tomography.

Positron emission tomography (PET) is becoming increasingly important in nuclear medicine and drug discovery. To date, the development of many potential PET tracers is hampered by the lack of suitable synthetic pathways for their preparation. This is particularly true for the highly desired radiolabeling of compounds bearing [F]CF-groups.

Synthesis and preclinical evaluation of [C]EAI045 as a PET tracer for imaging tumors expressing mutated epidermal growth factor receptor.

Background: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor's function. However, subsequent treatment resistance mutations in the ATP binding site are common.

Non-specific irreversible Zr-mAb uptake in tumours: evidence from biopsy-proven target-negative tumours using Zr-immuno-PET.

Background: Distribution of mAbs into tumour tissue may occur via different processes contributing differently to the Zr-mAb uptake on PET. Target-specific binding in tumours is of main interest; however, non-specific irreversible uptake may also be present, which influences quantification. The aim was to investigate the presence of non-specific irreversible uptake in tumour tissue using Patlak linearization on Zr-immuno-PET data of biopsy-proven target-negative tumours.

How to obtain the image-derived blood concentration from Zr-immuno-PET scans.

Background: PET scans using zirconium-89 labelled monoclonal antibodies (Zr-mAbs), known as Zr-immuno-PET, are made to measure uptake in tumour and organ tissue. Uptake is related to the supply of Zr-mAbs in the blood. Measuring activity concentrations in blood, however, requires invasive blood sampling.

Molecular imaging predicts lack of T-DM1 response in advanced HER2-positive breast cancer (final results of ZEPHIR trial).

Efficacy of the human epidermal growth factor receptor (HER)2-targeting trastuzumab emtansine (T-DM1) in breast cancer (BC) relies on HER2 status determined by immunohistochemistry or fluorescence in-situ hybridization. Heterogeneity in HER2 expression, however, generates interest in "whole-body" assessment of HER2 status using molecular imaging. We evaluated the role of HER2-targeted molecular imaging in detecting HER2-positive BC lesions and patients unlikely to respond to T-DM1.

Zr-Immuno-PET with Immune Checkpoint Inhibitors: Measuring Target Engagement in Healthy Organs.

Introduction: Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([Zr]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.

State of the art procedures towards reactive [F]fluoride in PET tracer synthesis.

Background: Positron emission tomography (PET) is a powerful, non-invasive preclinical and clinical nuclear imaging technique used in disease diagnosis and therapy assessment. Fluorine-18 is the predominant radionuclide used for PET tracer synthesis. An impressive variety of new 'late-stage' radiolabeling methodologies for the preparation of F-labeled tracers has appeared in order to improve the efficiency of the labeling reaction.

Synthesis and Preclinical Evaluation of [-C]brigatinib as a PET Tracer Targeting Both Mutated Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase.

Brigatinib, a tyrosine kinase inhibitor (TKI) with specificity for gene rearranged anaplastic lymphoma kinase (ALK), such as the EML4-ALK, has shown a potential to inhibit mutated epidermal growth factor receptor (EGFR). In this study, -desmethyl brigatinib was successfully synthesized as a precursor in five steps. Radiolabeling with [C]methyl iodide produced [-C]brigatinib in a 10 ± 2% radiochemical yield, 91 ± 17 GBq/μmol molar activity, and ≥95% radiochemical purity in 49 ± 4 min.

Synthesis and preclinical evaluation of two osimertinib isotopologues labeled with carbon-11 as PET tracers targeting the tyrosine kinase domain of the epidermal growth factor receptor.

Introduction: Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) that is able to inhibit the EGFR treatment resistance mutation T790M and primary EGFR mutations Del19 and L858R. The aim of the study was to evaluate the potential of carbon-11 labeled osimertinib to be used as a tracer for the PET imaging of tumors bearing the T790M mutation.

Methods: Osimertinib was labeled with carbon-11 at two positions, and the effect of the labeling position on the metabolism and biodistribution was studied in female nu/nu mice.

Zr-immuno-PET using the anti-LAG-3 tracer [Zr]Zr-BI 754111: demonstrating target specific binding in NSCLC and HNSCC.

Purpose: Although lymphocyte activation gene-3 (LAG-3) directed therapies demonstrate promising clinical anti-cancer activity, only a subset of patients seems to benefit and predictive biomarkers are lacking. Here, we explored the potential use of the anti-LAG-3 antibody tracer [Zr]Zr-BI 754111 as a predictive imaging biomarker and investigated its target specific uptake as well as the correlation of its tumor uptake and the tumor immune infiltration.

Methods: Patients with head and neck (N = 2) or lung cancer (N = 4) were included in an imaging substudy of a phase 1 trial with BI 754091 (anti-PD-1) and BI 754111 (anti-LAG-3).

Validation of simplified uptake measures against dynamic Patlak K for quantification of lesional Zr-Immuno-PET antibody uptake.

Purpose: Positron emission tomography imaging of zirconium-89-labelled monoclonal antibodies (Zr-Immuno-PET) allows for visualisation and quantification of antibody uptake in tumours in vivo. Patlak linearization provides distribution volume (V) and nett influx rate (K) values, representing reversible and irreversible uptake, respectively. Standardised uptake value (SUV) and tumour-to-plasma/tumour-to-blood ratio (TPR/TBR) are often used, but their validity depends on the comparability of plasma kinetics and clearances.