Biodistribution and Radiation Dosimetry for 68 Ga-DOTA-CCK-66, a Novel CCK 2 R-Targeting Compound for Imaging of Medullary Thyroid Cancer.

Abstract: Cholecystokinin 2 receptor (CCK 2 R) is a promising target for imaging and treatment of medullary thyroid cancer due to its overexpression in over 90% of tumor cells. 68 Ga-DOTA-CCK-66 is a recently introduced PET tracer selective for CCK 2 R, which has shown favorable pharmacokinetics in vivo in preclinical experiments. In order to further investigate safety and suitability of this tracer in the human setting, whole-body distribution and radiation dosimetry were evaluated.

Significant reduction of activity retention in the kidneys via optimized linker sequences in radiohybrid-based minigastrin analogs.

Background: We recently introduced radiohybrid (rh)-based minigastrin analogs e.g., DOTA-rhCCK-18 (DOTA-D-Dap(p-SiFA)-(D-γ-Glu)-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH), that revealed substantially increased activity retention in the tumor.

[Tc]Tc-PentixaTec: development, extensive pre-clinical evaluation, and first human experience.

Purpose: The clinical success non-invasive imaging of CXCR4 expression using [ Ga]Ga-PentixaFor-PET warrants an expansion of the targeting concept towards conventional scintigraphy/SPECT with their lower cost and general availability. To this aim, we developed and comparatively evaluated a series of Tc-labeled cyclic pentapeptides based on the PentixaFor scaffold.

Methods: Six mas-conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa linkers (L1-L6) as well as the corresponding HYNIC- and N-analogs of L6-CPCR4 were synthesized via standard SPPS.

Investigation of the structure-activity relationship at the N-terminal part of minigastrin analogs.

Background: Over the last years, several strategies have been reported to improve the metabolic stability of minigastrin analogs. However, currently applied compounds still reveal limited in vitro and in vivo stability. We thus performed a glycine scan at the N-terminus of DOTA-MGS5 (DOTA-D-Glu-Ala-Tyr-Gly-Trp-(N-Me)Nle-Asp-1-Nal) to systematically analyze the peptide structure.

Development of the First F-Labeled Radiohybrid-Based Minigastrin Derivative with High Target Affinity and Tumor Accumulation by Substitution of the Chelating Moiety.

In order to optimize elevated kidney retention of previously reported minigastrin derivatives, we substituted ()-DOTAGA by DOTA in ()-DOTAGA-rhCCK-16/-18. CCK-2R-mediated internalization and affinity of the new compounds were determined using AR42J cells. Biodistribution and SPECT/CT imaging studies at 1 and 24 h p.

Introduction of a SiFA Moiety into the D-Glutamate Chain of DOTA-PP-F11N Results in Radiohybrid-Based CCK-2R-Targeted Compounds with Improved Pharmacokinetics In Vivo.

In order to enable F- and Lu-labelling within the same molecule, we introduced a silicon-based fluoride acceptor (SiFA) into the hexa-D-glutamate chain of DOTA-PP-F11N. In addition, minigastrin analogues with a prolonged as well as -linked D-glutamate chain were synthesised and evaluated. CCK-2R affinity (, AR42J cells) and lipophilicity (log) were determined.

Albumin-Mediated Size Exclusion Chromatography: The Apparent Molecular Weight of PSMA Radioligands as Novel Parameter to Estimate Their Blood Clearance Kinetics.

A meticulously adjusted pharmacokinetic profile and especially fine-tuned blood clearance kinetics are key characteristics of therapeutic radiopharmaceuticals. We, therefore, aimed to develop a method that allowed the estimation of blood clearance kinetics in vitro. For this purpose, Lu-labeled PSMA radioligands were subjected to a SEC column with human serum albumin (HSA) dissolved in a mobile phase.

Optimization of the Pharmacokinetic Profile of [Tc]Tc-N-Bombesin Derivatives by Modification of the Pharmacophoric Gln-Trp Sequence.

Current radiolabeled gastrin-releasing peptide receptor (GRPR) ligands usually suffer from high accumulation in GRPR-positive organs (pancreas, stomach), limiting tumor-to-background contrast in the abdomen. In novel N4-bombesin derivatives this was addressed by substitutions at the Gln7-Trp8 site within the MJ9 peptide (H-Pip5-phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2) either by homoserine (Hse7), β-(3-benzothienyl) alanine (Bta8) or α-methyl tryptophan (α-Me-Trp8), with the aim of optimizing pharmacokinetics. We prepared and characterized the peptide conjugates 6-carboxy-1,4,8,11-tetraazaundecane (N4)-asp-MJ9, N4-asp-[Bta8]MJ9, N4-[Hse7]MJ9 and N4-[α-Me-Trp8]MJ9, and evaluated these compounds in vitro (GRPR affinity via IC50,inverse; internalization; lipophilicity via logD7.

Investigation of spleen CXCR4 expression by [Ga]Pentixafor PET in a cohort of 145 solid cancer patients.

Background: The chemokine receptor CXCR4 is frequently overexpressed and associated with adverse prognosis in most hematopoietic malignancies and solid cancers. Recently, CXCR4 molecular imaging using the CXCR4-specific positron emission tomography (PET) tracer Pentixafor ([Ga]Pentixafor) has become a well-established method to non-invasively measure CXCR4 expression in vivo. In previous Pentixafor imaging studies, highly variable CXCR4 tracer uptake to the spleen was observed.

Molecular Imaging of Inflammation and Fibrosis in Pressure Overload Heart Failure.

[Figure: see text].

CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas.

We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies.

CXCR4 PET imaging of mantle cell lymphoma using [Ga]Pentixafor: comparison with [F]FDG-PET.

For PET imaging of mantle cell lymphoma (MCL), [F]FDG (2-deoxy-2-[F]fluoro-D-glucose) is the currently recommended radiotracer, although uptake is variable and bone marrow evaluation is limited. In this prospective study, we evaluated the novel CXCR4 (G-protein-coupled C-X-C chemokine receptor type 4) tracer [Ga]Pentixafor in MCL patients, and compared it to [F]FDG. MCL patients underwent [Ga]Pentixafor-PET/MRI, and, if required for routine purposes, also [F]FDG-PET/MRI, before treatment.

[Ga]Ga-Pentixafor for PET Imaging of Vascular Expression of CXCR-4 as a Marker of Arterial Inflammation in HIV-Infected Patients: A Comparison with F[FDG] PET Imaging.

People living with human immunodeficiency virus (PLHIV) have excess risk of atherosclerotic cardiovascular disease (ASCVD). Arterial inflammation is the hallmark of atherogenesis and its complications. In this study we aimed to perform a head-to-head comparison of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([F]FDG PET/CT) and Gallium-68 pentixafor positron emission tomography/computed tomography [Ga]Ga-pentixafor PET/CT for quantification of arterial inflammation in PLHIV.

A new class of PentixaFor- and PentixaTher-based theranostic agents with enhanced CXCR4-targeting efficiency.

Non-invasive PET imaging of CXCR4 expression in cancer and inflammation as well as CXCR4-targeted radioligand therapy (RLT) have recently found their way into clinical research by the development of the theranostic agents [Ga]PentixaFor (cyclo(D-Tyr-D-[NMe]Orn(AMBS-[Ga]DOTA)-Arg-Nal-Gly) = [Ga]DOTA-AMBS-CPCR4) and [Lu/Y]PentixaTher (cyclo(D-3-iodo-Tyr-D-[NMe]Orn(AMBS-[Lu/Y]DOTA)-Arg-Nal-Gly) = [Lu/Y]DOTA-AMBS-CPCR4). Although convincing clinical results have already been obtained with both agents, this study was designed to further investigate the required structural elements for improved ligand-receptor interaction for both peptide cores (CPCR4 and CPCR4). To this aim, a series of DOTA-conjugated CPCR4- and CPCR4-based ligands with new linker structures, replacing the AMBA-linker in PentixaFor and PentixaTher, were synthesized and evaluated.

Radiohybrid Ligands: A Novel Tracer Concept Exemplified by F- or Ga-Labeled rhPSMA Inhibitors.

When we critically assess the reason for the current dominance of Ga-labeled peptides and peptide-like ligands in radiopharmacy and nuclear medicine, we have to conclude that the major advantage of such radiopharmaceuticals is the apparent lack of suitable F-labeling technologies with proven clinical relevance. To prepare and to subsequently perform a clinical proof-of-concept study on the general suitability of silicon-fluoride-acceptor (SiFA)-conjugated radiopharmaceuticals, we developed inhibitors of the prostate-specific membrane antigen (PSMA) that are labeled by isotopic exchange (IE). To compensate for the pronounced lipophilicity of the SiFA unit, we used metal chelates, conjugated in close proximity to SiFA.

Image-Guided Surgery: Are We Getting the Most Out of Small-Molecule Prostate-Specific-Membrane-Antigen-Targeted Tracers?

Expressed on virtually all prostate cancers and their metastases, the transmembrane protein prostate-specific membrane antigen (PSMA) provides a valuable target for the imaging of prostate cancer. Not only does PSMA provide a target for noninvasive diagnostic imaging, e.g.

PSMA-Targeted Radiopharmaceuticals for Imaging and Therapy.

As described in more detail in other contributions in this issue of Seminars in Nuclear Medicine, prostate-specific membrane antigen (PSMA) has become one of the most promising molecular targets in nuclear medicine. Due to its overexpression on prostate cancer cells in proportion to the stage and grade of tumour progression, especially in androgen-independent, advanced and metastatic disease, various tracers for the detection and treatment of prostate cancer by means of radioligand imaging, radioligand therapy or radioguided surgery have been developed and transferred to clinical applications. Even though monoclonal antibodies were investigated and introduced as first PSMA-targeted probes, the inherent advantage of fast tumour uptake and rapid excretion of small molecules has shifted the research focus during the last decade to low molecular weight inhibitors with high affinity to PSMA, such as [F]FDCFPyL, [F]PSMA-1007, [Ga]PSMA-HBED, [Lu]PSMA-617, [Lu]PSMA-I&T, [Tc]MIP-1404 or [Tc]PSMA I&S, to mention only a few.

Clinical Effects of Perioperative Selective Decontamination of the Digestive Tract (SDD) in Cardiac Surgery: A Propensity Score Matched Cohort Analysis.

Objectives: To determine the clinical effects of perioperative endotoxin reduction in the gut lumen in patients undergoing cardiac surgery with cardiopulmonary bypass.

Design: Retrospective cohort analysis with propensity score matching according to treatment group.

Setting: Tertiary center for cardiopulmonary diseases and intensive care medicine.

International Union of Basic and Clinical Pharmacology. CV. Somatostatin Receptors: Structure, Function, Ligands, and New Nomenclature.

Somatostatin, also known as somatotropin-release inhibitory factor, is a cyclopeptide that exerts potent inhibitory actions on hormone secretion and neuronal excitability. Its physiologic functions are mediated by five G protein-coupled receptors (GPCRs) called somatostatin receptor (SST)1-5. These five receptors share common structural features and signaling mechanisms but differ in their cellular and subcellular localization and mode of regulation.

Targeting Chemokine Receptor CXCR4 and Translocator Protein for Characterization of High-Risk Plaque in Carotid Stenosis Ex Vivo.

Background and Purpose- This pilot study aims to demonstrate the feasibility of targeting molecular characteristics of high-risk atherosclerotic plaque in symptomatic and asymptomatic carotid stenosis (CS), that is, upregulation of the translocator protein (TSPO) and the chemokine receptor type 4 (CXCR4), by means of molecular imaging. Methods- In a translational setting, specimens of carotid plaques of patients with symptomatic and asymptomatic CS obtained by carotid endarterectomy were analyzed for the presence of TSPO and CXCR4 by autoradiography, using the positron emission tomography tracers F-GE180 and Ga-Pentixafor and evaluated by histopathology. In addition, Ga-Pentixafor positron emission tomography/computed tomography was performed in a patient with high-grade CS.

Dual Targeting of Acute Leukemia and Supporting Niche by CXCR4-Directed Theranostics.

C-X-C chemokine receptor 4 (CXCR4) is a transmembrane receptor with pivotal roles in cell homing and hematopoiesis. CXCR4 is also involved in survival, proliferation and dissemination of cancer, including acute lymphoblastic and myeloid leukemia (ALL, AML). Relapsed/refractory ALL and AML are frequently resistant to conventional therapy and novel highly active strategies are urgently needed to overcome resistance.

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma.

Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools.

Exploring the Role of RGD-Recognizing Integrins in Cancer.

Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions.

Theranostic Value of Multimers: Lessons Learned from Trimerization of Neurotensin Receptor Ligands and Other Targeting Vectors.

Neurotensin receptor 1 (NTS1) is overexpressed on a variety of cancer entities; for example, prostate cancer, ductal pancreatic adenocarcinoma, and breast cancer. Therefore, it represents an interesting target for the diagnosis of these cancers types by positron emission tomography (PET) [..

Evaluation of 68Ga-Glutamate Carboxypeptidase II Ligand Positron Emission Tomography for Clinical Molecular Imaging of Atherosclerotic Plaque Neovascularization.

Objective: Intraplaque neovascularization contributes to the progression and rupture of atherosclerotic lesions. Glutamate carboxypeptidase II (GCPII) is strongly expressed by endothelial cells of tumor neovasculature and plays a major role in hypoxia-induced neovascularization in rodent models of benign diseases. We hypothesized that GCPII expression may play a role in intraplaque neovascularization and may represent a target for imaging of atherosclerotic lesions.