Synthesis and Structure-Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography.

The costimulatory molecule CD80 is an early marker for immune activation. It is upregulated on activated antigen-presenting cells. We aimed at developing a tracer for imaging CD80 by positron emission tomography (PET).

Preclinical investigations and first-in-human application of Tb-PSMA-617 for PET/CT imaging of prostate cancer.

Background: For almost a decade, terbium radioisotopes have been explored for their potential theragnostic application in nuclear medicine: Tb and Tb are the radioisotopes identified for PET or SPECT imaging, while Tb and Tb have suitable decay characteristics for α- and combined β/Auger-e-therapy, respectively. In the present study, the application of Tb, in combination with PSMA-617 for imaging of prostate-specific membrane antigen (PSMA)-positive prostate cancer, was demonstrated in a preclinical setting and in a patient with metastatic castration-resistant prostate cancer (mCRPC).

Results: Tb was produced at the ISOLDE facility at CERN/Geneva, Switzerland, by spallation, followed by on-line mass separation.

Concentration-dependent effects of dutasteride on prostate-specific membrane antigen (PSMA) expression and uptake of Lu-PSMA-617 in LNCaP cells.

Background: Prostate-specific membrane antigen (PSMA)-based imaging and therapy are increasingly used in the management of prostate cancer. However, low PSMA surface expression in certain patients is a limitation for PSMA-based technologies. We have previously shown that high doses of dutasteride, a 5α-reductase inhibitor generally used for the treatment of benign prostatic enlargement, increase the PSMA expression in vitro.

Internal radiation dosimetry of a Tb-labeled antibody in tumor-bearing mice.

Background: Biodistribution studies based on organ harvesting represent the gold standard pre-clinical technique for dose extrapolations. However, sequential imaging is becoming increasingly popular as it allows the extraction of longitudinal data from single animals, and a direct correlation with deterministic radiation effects. We assessed the feasibility of mouse-specific, microPET-based dosimetry of an antibody fragment labeled with the positron emitter Tb [(T = 17.

Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer.

Purpose: The prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate Tb (T = 6.89 days; Eβ = 154 keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to Lu-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.

Exendin-4 analogs in insulinoma theranostics.

Insulinomas, neuroendocrine tumors arising from pancreatic beta cells, often show overexpression of the glucagon-like peptide-1 receptor. Therefore, imaging with glucagon-like peptide analog exendin-4 can be used for diagnosis and preoperative localization. This review presents an overview of the development and clinical implementation of exendin-based tracers for nuclear imaging, and the potential use of exendin-4 based tracers for optical imaging and therapeutic applications such as peptide receptor radionuclide therapy or targeted photodynamic therapy.

Recent progress in allosteric modulators for GluN2A subunit and development of GluN2A-selective nuclear imaging probes.

N-methyl-D-aspartate (NMDA) receptors play key roles in physiology by regulating the synaptic plasticity and the cellular mechanism involved in learning and memory. The GluN2A subunit is the most abundant expression of NMDA receptors in mature brain, and its dysfunction has been implicated in various neurological disorders. However, the function of GluN2A subunit in physiological and pathological conditions is not yet completely unveil due to the lack of subunit-selective ligands, including specific positron emission tomography (PET)/single photon emission computed tomography (SPECT) imaging probes.

Implementation of a new separation method to produce qualitatively improved Cu.

Background: Cu (T  = 12.7 h) is an important radionuclide for diagnostic purposes and used for positron emission tomography (PET). A previous method utilized at Paul Scherrer Institute (PSI) proved to be unreliable and, while a method using anion exchange chromatography is a popular choice worldwide, it was felt a different approach was required to obtain a robust chemical separation method.

First Clinicopathologic Evidence of a Non-PSMA-Related Uptake Mechanism for Ga-PSMA-11 in Salivary Glands.

The intense accumulation of prostate-specific membrane antigen (PSMA) radioligands in salivary glands is still not well understood. It is of concern for therapeutic applications of PSMA radioligands, because therapeutic radiation will damage these glands. A better understanding of the uptake mechanism is, therefore, crucial to find solutions to reduce toxicity.

In Vivo Labeling of Plasma Proteins for Imaging of Enhanced Vascular Permeability in the Lungs.

Increased vascular permeability is an important hallmark of many diseases, including cancer, cerebral ischemia, and severe inflammatory disorders. In this regard, the noninvasive assessment of pathologically increased vascular permeability in vivo is of great interest. In this study, the potential of albumin- and transthyretin-binding radioligands was evaluated for imaging of vascular hyperpermeability.

Combination of lutetium-177 labelled anti-L1CAM antibody chCE7 with the clinically relevant protein kinase inhibitor MK1775: a novel combination against human ovarian carcinoma.

Background: Protein kinase inhibitors (PKIs) are currently tested in clinical studies (phase I-III) as an alternative strategy against (recurrent) ovarian cancer. Besides their anti-tumour efficacy, several PKIs have also shown radiosensitizing effects when combined with external beam radiation. Based on these results we asked if the addition of PKIs offers a therapeutic opportunity to improve radioimmunotherapy (RIT) against ovarian cancer.

Diastereomerically Pure 6- and 6-3'-Aza-2'-F-Fluoro-5-Methyltetrahydrofolates Show Unprecedentedly High Uptake in Folate Receptor-Positive KB Tumors.

The aim of this study was to develop the radiosyntheses of diastereomerically pure 6- and 6-3'-aza-2'-F-fluoro-5-methyltetrahydrofolate (MTHF) (6-F- and 6-F-) using the integrated approach and to compare the in vitro and in vivo performance characteristics of both radioligands with the previously reported 3'-aza-2'-F-fluorofolic acid tracer (F-), the oxidized form. 6-F- 6-F- and F- were radiolabeled with F using aromatic nucleophilic substitution reaction. In vitro cell uptake studies and binding affinity assays were performed using folate receptor (FR)-α-expressing KB cells.

Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates.

Folic-acid-based radioconjugates have been developed for nuclear imaging of folate receptor (FR)-positive tumors; however, high renal uptake was unfavorable in view of a therapeutic application. Previously, it was shown that pre-injection of pemetrexed (PMX) increased the tumor-to-kidney ratio of radiofolates several-fold. In this study, PMX was combined with the currently best performing radiofolate ([Lu]cm13), which is outfitted with an albumin-binding entity.

Preclinical Development of Novel PSMA-Targeting Radioligands: Modulation of Albumin-Binding Properties To Improve Prostate Cancer Therapy.

The treatment of metastatic castration-resistant prostate cancer (mCRPC) remains challenging with current treatment options. The development of more effective therapies is, therefore, urgently needed. Targeted radionuclide therapy with prostate-specific membrane antigen (PSMA)-targeting ligands has revealed promising clinical results.

Scandium and terbium radionuclides for radiotheranostics: current state of development towards clinical application.

Currently, different radiometals are in use for imaging and therapy in nuclear medicine: Ga and In are examples of nuclides for positron emission tomography (PET) and single photon emission computed tomography (SPECT), respectively, while Lu and Ac are used for β- and α-radionuclide therapy. The application of diagnostic and therapeutic radionuclides of the same element (radioisotopes) would utilize chemically-identical radiopharmaceuticals for imaging and subsequent treatment, thereby enabling the radiotheranostic concept. There are two elements which are of particular interest in this regard: Scandium and Terbium.

Pharmacological upregulation of prostate-specific membrane antigen (PSMA) expression in prostate cancer cells.

Background: Prostate-specific membrane antigen (PSMA)-based imaging and therapy are increasingly used for prostate cancer management. However, limitations are a low PSMA expression in certain patients. Androgen receptor axis inhibition can induce PSMA expression in vitro.

Reduced F-Folate Conjugates as a New Class of PET Tracers for Folate Receptor Imaging.

5-Methyltetrahydrofolate (5-MTHF), a reduced folate form, is the biologically active folate involved in many different metabolic processes. To date, there are no studies available in the literature on F-labeled 6 S- and 6 R-5-MTHF radiotracers for imaging folate receptor (FR)-α-positive tissues. Therefore, the goal of this study was to synthesize four F-labeled 5-MTHF derivatives conjugated at either the α- or γ-carboxylic functionality of glutamate and to assess their suitability for FR-targeting.

Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile.

The prostate-specific membrane antigen (PSMA) has emerged as an attractive prostate cancer associated target for radiotheragnostic application using PSMA-specific radioligands. The aim of this study was to design new PSMA ligands modified with an albumin-binding moiety in order to optimize their tissue distribution profile. The compounds were prepared by conjugation of a urea-based PSMA-binding entity, a DOTA chelator, and 4-( p-iodophenyl)butyric acid using multistep solid phase synthesis.

Enhanced Specific Activity by Multichelation of Exendin-3 Leads To Improved Image Quality and In Vivo Beta Cell Imaging.

Glucagon-like peptide-1 receptor (GLP-1R) targeting using radiolabeled exendin is a promising approach to noninvasively visualize and determine beta cell mass (BCM), which could help to unravel the pathophysiology of diabetes. However, saturation of the GLP-1R on beta cells occurs at low peptide doses, since the number of receptors expressed under physiological conditions is low. Therefore, tracers with high specific activities are required to sensitively image small variations in BCM.

Synthesis, Radiolabeling, and Characterization of Plasma Protein-Binding Ligands: Potential Tools for Modulation of the Pharmacokinetic Properties of (Radio)Pharmaceuticals.

The development of (radio)pharmaceuticals with favorable pharmacokinetic profiles is crucial for allowing the optimization of the imaging or therapeutic potential and the minimization of undesired side effects. The aim of this study was, therefore, to evaluate and compare three different plasma protein binders (PPB-01, PPB-02, and PPB-03) that are potentially useful in combination with (radio)pharmaceuticals to enhance their half-life in the blood. The entities were functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator via a l-lysine and β-alanine linker moiety using solid-phase peptide chemistry and labeled with Lu (T = 6.

Therapeutic Radiometals Beyond Lu and Y: Production and Application of Promising α-Particle, β-Particle, and Auger Electron Emitters.

In recent years, new α-particle-, β-particle-, and Auger electron-emitting radiometals-such as Cu, Sc, Ho, Tb, Tb, Pb/Bi, Ac, and Bi-have been produced and evaluated (pre)clinically for therapeutic purposes. In this short review article, the most important routes of production of these radiometals are critically discussed, as are examples of their application in preclinical and clinical studies.

Glu-Ureido-Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers.

In recent years, several radioligands targeting prostate-specific membrane antigen (PSMA) have been clinically introduced as a new class of theranostic radiopharmaceuticals for the treatment of prostate cancer (PC). In the second decade of the 21 century, a new era in nuclear medicine was initiated by the clinical introduction of small-molecule PSMA inhibitor radioligands, 40 y after the clinical introduction of F-FDG. Because of the high incidence and mortality of PC, the new PSMA radioligands have already had a remarkable impact on the clinical management of PC.

Clinical evaluation of the radiolanthanide terbium-152: first-in-human PET/CT with Tb-DOTATOC.

The existence of theragnostic pairs of radionuclides allows the preparation of radiopharmaceuticals for diagnostic and therapeutic purposes. Radiolanthanides, such as Lu, are successfully used for therapeutic purposes; however, a perfect diagnostic match is currently not available for clinical use. A unique, multi-disciplinary study was performed using Tb (T = 17.

Folate Receptor-Positive Gynecological Cancer Cells: In Vitro and In Vivo Characterization.

The folate receptor (FR) is expressed in a variety of gynecological cancer types. It has been widely used for tumor targeting with folic acid conjugates of diagnostic and therapeutic probes. The cervical KB tumor cells have evolved as the standard model for preclinical investigations of folate-based (radio) conjugates.