Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

In this study, a significantly improved method for the synthesis of modular meso-BODIPY (boron dipyrromethene) derivatives possessing a free carboxylic acid group (which was subsequently coupled to peptides), is disclosed. This method provides a vastly efficient synthetic route with a > threefold higher overall yield than other reports. The resultant meso-BODIPY acid allowed for further easy incorporation into peptides. The meso-BODIPY peptides showed absorption maxima from 495–498 nm and emission maxima from 504–506 nm, molar absorptivity coefficients from 33 383–80 434 M⁻¹ cm⁻¹ and fluorescent quantum yields from 0.508–0.849. The meso-BODIPY-c(RGDyK) peptide was evaluated for plasma stability and (proved to be durable even up to 4 h) was then assessed for its fluorescence imaging applicability in vivo and ex vivo. The optical imaging in vivo was limited due to autofluorescence, however, the ex vivo tissue analysis displayed BODIPY-c(RGDyK) internalization and cancer detection thereby making it a novel tumor-integrin associated fluorescent probe while displaying the lack of interference the dye has on the properties of this ligand to bind the receptor.

Despite numerous innovative treatment strategies, the treatment of glioblastoma (GB) remains challenging. With the current state-of-the-art therapy, most GB patients succumb after about a year. In the evolution of personalized medicine, targeted radionuclide therapy (TRT) is gaining momentum, for example, to stratify patients based on specific biomarkers. One of these biomarkers is deficiencies in DNA damage repair (DDR), which give rise to genomic instability and cancer initiation. However, these deficiencies also provide targets to specifically kill cancer cells following the synthetic lethality principle. This led to the increased interest in targeted drugs that inhibit essential DDR kinases (DDRi), of which multiple are undergoing clinical validation. In this review, the current status of DDRi for the treatment of GB is given for selected targets: ATM/ATR, CHK1/2, DNA-PK, and PARP. Furthermore, this review provides a perspective on the use of radiopharmaceuticals targeting these DDR kinases to (1) evaluate the DNA repair phenotype of GB before treatment decisions are made and (2) induce DNA damage via TRT. Finally, by applying in-house selection criteria and analyzing the structural characteristics of the DDRi, four drugs with the potential to become new therapeutic GB radiopharmaceuticals are suggested.

The limited use of palladium‐103 and ‐109 radionuclides for molecular radiotherapy is surely due to the lack of appropriate ligands capable of fulfilling all criteria required for application in nuclear medicine. Furthermore, the thermodynamic properties of these complexes in solution remain difficult to establish. The challenge is compounded when considering that radiolabeling of compounds for translation to clinical trials requires fast complexation. Thus, the coordination of Pd(II) and ^103/109Pd‐nuclides is a huge challenge in terms of molecular design and physicochemical characterization. Herein, we report a comprehensive study highlighting TE1PA, a monopicolinate cyclam – already established in nuclear imaging with ⁶⁴Cu‐PET (positron emission tomography) imaging tracers – as a highly relevant chelator for natural Pd and subsequently ¹⁰⁹Pd‐nuclide. The structural, thermodynamic, kinetic and radiolabeling studies of Pd(II) with TE1PA, as well as the comparison of this complex with three structurally related derivatives, support palladium‐TE1PA radiopharmaceuticals as leading candidates for targeted nuclear medicine.

Two bifunctional copper chelators H ₂ TE1PA-trz-prA and H ₂ CB-TE1PA-trz-prA were synthesized and their relevant ^nat Cu- and ⁶⁴ Cu-complex properties highlighted.

Background/Objectives: The ¹⁰³Pd/^103mRh in vivo generator represents a promising Auger electron-emitting system, in which both parent and daughter radionuclides emit predominantly Auger electrons with minimal accompanying radiation. This study investigates the release dynamics of daughter radionuclides from the ¹⁰³Pd/^103mRh in vivo generator and evaluates the underlying mechanisms governing bond rupture and daughter retention. Methods: Cyclotron irradiation of rhodium foils was performed in two separate batches, followed by radionuclide separation using conventional wet chemistry and a novel dry distillation technique. The purified ¹⁰³Pd radionuclide was used to radiolabel DOTA-TATE, phthalocyanine-TATE, and DOTA-TOC chelators. The resulting complexes were immobilized on Strata-X and Strata-C18 solid-phase extraction columns. Scheduled elution experiments were conducted to quantify the release of the ^103mRh daughter radionuclide. Results: The measured ^103mRh release rates were 9.8 ± 3.0% and 9.6 ± 2.7% from Strata-X columns with DOTA-TATE and phthalocyanine-TATE, respectively, and 10.5 ± 2.7% and 12.0 ± 0.5% from Strata-X and Strata-C18 columns, respectively, with DOTA-TOC. These values are significantly lower than the ~100% release predicted based on the reported Auger electron yield of 186%. One explanation for this difference could be potential inconsistencies in decay data that may require correction; this needs further investigation. The results further demonstrated that delocalized π-electrons, introduced via phthalocyanine-based chelation, did not mitigate daughter release. Conclusions: The low observed daughter nuclide release represents a favorable characteristic for the future clinical translation of the ¹⁰³Pd/^103mRh Auger emitter pair. The findings support the conclusion that Auger electron cascades, rather than nuclear recoil energy, dominate bond rupture processes.