Are heterobivalent GRPR- and VPAC1R-bispecific radiopeptides suitable for efficient in vivo tumor imaging of prostate carcinomas?

Receptor-specific peptides labeled with positron emitters play an important role in the clinical imaging of several malignancies by positron emission tomography (PET). Radiolabeled heterobivalent bispecific peptidic ligands (HBPLs) can target more than one receptor type and by this - besides exhibiting other advantages - increase tumor imaging sensitivity. In the present study, we show the initial in vivo evaluation of the most potent heterobivalent gastrin-releasing peptide receptor (GRPR)- and vasoactive intestinal peptide receptor subtype 1 (VPAC1R)-bispecific radiotracer and determined its tumor visualization potential via PET/CT imaging. For this purpose, the most potent described HBPL was synthesized together with its partly scrambled heterobivalent monospecific homologs and its monovalent counterparts. The agents were efficiently labeled with 68Ga3+ and evaluated in an initial PET/CT tumor imaging study in a human prostate carcinoma (PCa) xenograft rat tumor model established for this purpose. None of the three 68Ga-HBPLs enabled a clear tumor visualization and a considerably higher involvement in receptor-mediated uptake was found for the GRPR-binding part of the molecule than for the VPAC1R-binding one. Of the monovalent radiotracers, only [68Ga]Ga-NODA-GA-PESIN could efficiently delineate the tumor, confirming the results. Thus, this work sets the direction for future developments in the field of GRPR- and VPAC1R-bispecific radioligands, which should be based on other VPAC1R-specific peptides than PACAP-27.

Bispidine dioxotetraaza macrocycles: a new class of bispidines for (64)Cu PET imaging.

The three new dioxo-tetraazamacrocyclic ligands with a fused, very rigid bispidine (3,7-diazabicyclo[3.3.1]nonane) group connecting the two tertiary amine donors, and ethyl, propyl, or benzene groups connecting the two amide donors are highly preorganized and lead to very stable, uncharged Cu(II) complexes. Solution spectroscopy and solid state structures indicate that these are square pyramidal with a solvent molecule occupying the apical position. Cyclic voltammetry defines a reversible Cu(III/II) couple and a strongly negative irreversible Cu(II/I) couple (ca. -2 V vs Fc/Fc(+)), indicating that the Cu(II) complexes are very stable in solution. This is supported by superoxide dismutase (SOD) and human serum challenge experiments as well as the biodistribution, which all show that the benzene-based ligand has the highest in vitro and in vivo stability and that this was expected on the basis of the macrocycle ring size and shape and the highest degree of preorganization. This ligand is easy to functionalize for a possible coupling to biological vector molecules and/or fluorescence markers for PET (positron emission tomography) and multimodal imaging (i.e., PET and optical imaging).

Comparing quantitative image parameters between animal and clinical CT-scanners: a translational phantom study analysis.

Purpose: This study compares phantom-based variability of extracted radiomics features from scans on a photon counting CT (PCCT) and an experimental animal PET/CT-scanner (Albira II) to investigate the potential of radiomics for translation from animal models to human scans. While oncological basic research in animal PET/CT has allowed an intrinsic comparison between PET and CT, but no 1:1 translation to a human CT scanner due to resolution and noise limitations, Radiomics as a statistical and thus scale-independent method can potentially close the critical gap. Methods: Two phantoms were scanned on a PCCT and animal PET/CT-scanner with different scan parameters and then the radiomics parameters were extracted. A Principal Component Analysis (PCA) was conducted. To overcome the limitation of a small dataset, a data augmentation technique was applied. A Ridge Classifier was trained and a Feature Importance- and Cluster analysis was performed. Results: PCA and Cluster Analysis shows a clear differentiation between phantom types while emphasizing the comparability of both scanners. The Ridge Classifier exhibited a strong training performance with 93% accuracy, but faced challenges in generalization with a test accuracy of 62%. Conclusion: These results show that radiomics has great potential as a translational tool between animal models and human routine diagnostics, especially using the novel photon counting technique. This is another crucial step towards integration of radiomics analysis into clinical practice.

Synthesis and transition metal coordination chemistry of a novel hexadentate bispidine ligand.

Reported is the new bispidine-derived hexadentate ligand (L = 3-(2-methylpyridyl)-7-(bis-2-methylpyridyl)-3,7-diazabicyclo[3.3.1]nonane) with two tertiary amine and four pyridine donor groups. This ligand can form heterodinuclear and mononuclear complexes and, in the mononuclear compounds discussed here, the ligand may coordinate as a pentadentate ligand, with one of the bispyridinemethane-based pyridine groups un- or semi-coordinated, or as a hexadentate ligand, leading to a pentagonal pyramidal coordination geometry or, with an additional monodentate ligand, to a heptacoordinate pentagonal bipyramidal structure. The solution and solid state data presented here indicate that, with the relatively small Cu(II) and high-spin Fe(II) ions the fourth pyridine group is only semi-coordinated for steric reasons and, with the larger high-spin Mn(II) ion genuine heptacoordination is observed but with a relatively large distortion in the pentagonal equatorial plane.