Receptor-Targeted Peptide Conjugates Based on Diphosphines Enable Preparation of Tc and Re Theranostic Agents for Prostate Cancer.

Benchtop Mo/Tc and W/Re generators enable economical production of molecular theranostic Tc and Re radiopharmaceuticals, provided that simple, kit-based chemistry exists to radiolabel targeting vectors with these radionuclides. We have previously described a diphosphine platform that efficiently incorporates Tc into receptor-targeted peptides. Here, we report its application to label a prostate-specific membrane antigen (PSMA)-targeted peptide with Tc and Re for diagnostic imaging and systemic radiotherapy of prostate cancer.

Selection of radionuclide(s) for targeted alpha therapy based on their nuclear decay properties.

Targeted alpha therapy (TAT) is a promising form of oncology treatment utilising alpha-emitting radionuclides that can specifically accumulate at disease sites. The high energy and high linear energy transfer associated with alpha emissions causes localised damage at target sites whilst minimising that to surrounding healthy tissue. The lack of appropriate radionuclides has inhibited research in TAT.

Versatile Diphosphine Chelators for Radiolabeling Peptides with Tc and Cu.

We have developed a diphosphine (DP) platform for radiolabeling peptides with Tc and Cu for molecular SPECT and PET imaging, respectively. Two diphosphines, 2,3-bis(diphenylphosphino)maleic anhydride (DP) and 2,3-bis(di--tolylphosphino)maleic anhydride (DP), were each reacted with a Prostate Specific Membrane Antigen-targeted dipeptide (PSMAt) to yield the bioconjugates DP-PSMAt and DP-PSMAt, as well as an integrin-targeted cyclic peptide, RGD, to yield the bioconjugates DP-RGD and DP-RGD. Each of these DP-PSMAt conjugates formed geometric /-[MO(DP-PSMAt)] (M = Tc, Tc, Re; X = Ph, Tol) complexes when reacted with [MO] motifs.

PSMA-targeted NIR probes for image-guided detection of prostate cancer.

Tumour-targeted near-infrared (NIR) optical imaging is an emerging tool for the detection of malignant tissues. This modality can be useful in both diagnosis and intraoperative visualisation, to help defining tumour margins and allow a more precise removal of all the cancerous mass during surgery. In this context, we have developed a series of NIR fluorescent probes that target the prostate-specific membrane antigen (PSMA), an established biomarker overexpressed in prostate cancer.

An overview of nuclear medicine research in the UK and the landscape for clinical adoption.

Background And Objectives: Nuclear medicine contributes greatly to the clinical management of patients and experimental medicine. This report aims to (1) outline the current landscape of nuclear medicine research in the UK, including current facilities and recent or ongoing clinical studies and (2) provide information about the available pathways for clinical adoption and NHS funding (commissioning) of radiopharmaceuticals.

Methods: Evidence was obtained through database searches for UK-based nuclear medicine clinical studies and by conducting a questionnaire-based survey of UK radiopharmaceutical production facilities.

Dipeptide inhibitors of the prostate specific membrane antigen (PSMA): A comparison of urea and thiourea derivatives.

Glutamate carboxypeptidase II (GCP(II)), also known as the prostate-specific membrane antigen (PSMA), is a transmembrane zinc(II) metalloenzyme overexpressed in prostate cancer. Inhibitors of this receptor are used to target molecular imaging agents and molecular radiotherapy agents to prostate cancer and if the affinity of inhibitors for GCP(II)/PSMA could be improved, targeting might also improve. Compounds containing the dipeptide OH-Lys-C(O)-Glu-OH (compound 3), incorporating a urea motif, have high affinity for GCP(II)/PSMA.

The effects of trace metal impurities on Ga-68-radiolabelling with a tris(3-hydroxy-1,6-dimethylpyridin-4-one) (THP) chelator.

GMP-grade Ge/Ga generators provide access to positron-emitting Ga, enabling preparation of Positron Emission Tomography (PET) tracers and PET imaging at sites that do not have access to cyclotron-produced radionuclides. Radiotracers based on tris(3-hydroxy-1,6-dimethylpyridin-4-one) (THP) chelators enable simple one-step preparations of Ga PET radiopharmaceuticals from pre-fabricated kits without pre-processing of generator eluate or post-purification. However, trace metal impurities eluted along with Ga could compete for THP and reduce radiochemical yields (RCY).

Tuning the properties of tris(hydroxypyridinone) ligands: efficient Ga chelators for PET imaging.

The prototype tris(1,6-dimethyl-3-hydroxypyridin-4-one) chelator for gallium-68, THPMe, has shown great promise for rapid and efficient kit-based 68Ga labelling of PET radiopharmaceuticals. Peptide derivatives of THPMe have been used to image expression of their target receptors in vivo in preclinical and clinical studies. Herein we describe new synthetic routes to the THP platform including replacing the 1,6-dimethyl-3-hydroxypyridin-4-one N1-CH3 group of THPMe with O (tris(6-methyl-3-hydroxypyran-4-one, THPO) and N1-H (tris(6-methyl-3-hydroxypyridin-4-one), THPH) groups.

Comparison of macrocyclic and acyclic chelators for gallium-68 radiolabelling.

Gallium-68 (Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression. Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting biomolecules tethered to chelators that complex Ga. Ideally, the chelator will rapidly, quantitatively and stably coordinate Ga at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation.

Cold Kit for Prostate-Specific Membrane Antigen (PSMA) PET Imaging: Phase 1 Study of Ga-Tris(Hydroxypyridinone)-PSMA PET/CT in Patients with Prostate Cancer.

Ga-labeled urea-based inhibitors of the prostate-specific membrane antigen (PSMA), such as Ga-labeled ,'-bis(2-hydroxybenzyl)ethylenediamine-,'-diacetic acid (HBED)-PSMA-11, are promising small molecules for targeting prostate cancer. A new radiopharmaceutical, Ga-labeled tris(hydroxypyridinone) (THP)-PSMA, has a simplified design for single-step kit-based radiolabeling. It features the THP ligand, which forms complexes with Ga rapidly at a low concentration, at room temperature, and over a wide pH range, enabling direct elution from a Ge/Ga generator into a lyophilized radiopharmaceutical kit in 1 step without manipulation.

Ga-THP-PSMA: A PET Imaging Agent for Prostate Cancer Offering Rapid, Room-Temperature, 1-Step Kit-Based Radiolabeling.

The clinical impact and accessibility of Ga tracers for the prostate-specific membrane antigen (PSMA) and other targets would be greatly enhanced by the availability of a simple, 1-step kit-based labeling process. Radiopharmacy staff are accustomed to such procedures in the daily preparation of Tc radiopharmaceuticals. Currently, chelating agents used in Ga radiopharmaceuticals do not meet this ideal.

[(18)F]tetrafluoroborate as a PET tracer for the sodium/iodide symporter: the importance of specific activity.

Background: [(18)F]BF4 (-), the first (18)F-labelled PET imaging agent for the sodium/iodide symporter (NIS), was produced by isotopic exchange yielding a product with limited specific activity (SA, ca. 1 GBq/μmol) posing a risk of sub-optimal target-to-background ratios (TBR) in PET images due to saturation of NIS in vivo. We sought to quantify this risk and to develop a method of production of [(18)F]BF4 (-) with higher SA.

Opportunities and challenges for metal chemistry in molecular imaging: from gamma camera imaging to PET and multimodality imaging.

The development of medical imaging is a highly multidisciplinary endeavor requiring the close cooperation of clinicians, physicists, engineers, biologists and chemists to identify capabilities, conceive challenges and solutions and apply them in the clinic. The chemistry described in this article illustrates how synergistic advances in these areas drive the technology and its applications forward, with each discipline producing innovations that in turn drive innovations in the others. The main thread running through the article is the shift from single photon radionuclide imaging towards PET, and in turn the emerging shift from PET/CT towards PET/MRI and further, combination of these with optical imaging.