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.

Preclinical comparison of [Lu]Lu-rhPSMA-10.1 and [Lu]Lu-rhPSMA-10.2 for endoradiotherapy of prostate cancer: biodistribution and dosimetry studies.

Background: Radiohybrid PSMA-targeted ligands (rhPSMA) have been introduced as a novel platform for theranostic applications. Among a variety of rhPSMA-ligands developed for radioligand therapy, two stereoisomers [Lu]Lu-rhPSMA-10.1 and -10.

Heterogeneity of prostate-specific membrane antigen (PSMA) and PSMA-ligand uptake detection combining autoradiography and postoperative pathology in primary prostate cancer.

Background: Targeting prostate-specific membrane antigen (PSMA) has been highly successful for imaging and treatment of prostate cancer. However, heterogeneity in immunohistochemistry indicates limitations in the effect of imaging and radionuclide therapy of multifocal disease. Tc-PSMA-I&S is a γ-emitting probe, which can be used for intraoperative lesion detection and postsurgical autoradiography (ARG).

Preclinical Evaluation of Minigastrin Analogs and Proof-of-Concept [Ga]Ga-DOTA-CCK-66 PET/CT in 2 Patients with Medullary Thyroid Cancer.

Because of the need for radiolabeled theranostics for the detection and treatment of medullary thyroid cancer (MTC), and the yet unresolved stability issues of minigastrin analogs targeting the cholecystokinin-2 receptor (CCK-2R), our aim was to address in vivo stability, our motivation being to develop and evaluate DOTA-CCK-66 (DOTA-γ-glu-PEG-Trp-(-Me)Nle-Asp-1-Nal-NH, PEG: polyethylene glycol) and DOTA-CCK-66.2 (DOTA-glu-PEG-Trp-(-Me)Nle-Asp-1-Nal-NH), both derived from DOTA-MGS5 (DOTA-glu-Ala-Tyr-Gly-Trp-(-Me)Nle-Asp-1-Nal-NH), and clinically translate [Ga]Ga-DOTA-CCK-66. Cu and Ga labeling of DOTA-CCK-66, DOTA-CCK-66.

Preclinical Comparison of the Cu- and Ga-Labeled GRPR-Targeted Compounds RM2 and AMTG, as Well as First-in-Humans [Ga]Ga-AMTG PET/CT.

Despite the recent success of prostate-specific membrane antigen (PSMA)-targeted compounds for theranostic use in prostate cancer (PCa), alternative options for the detection and treatment of PSMA-negative lesions are needed. We have recently developed a novel gastrin-releasing peptide receptor (GRPR) ligand with improved metabolic stability, which might improve diagnostic and therapeutic efficacy and could be valuable for PSMA-negative PCa patients. Our aim was to examine its suitability for theranostic use.

[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.

CXCR4-Directed Imaging and Endoradiotherapy in Desmoplastic Small Round Cell Tumors.

Desmoplastic small round cell tumor (DSRCT) is a rare, radiosensitive, yet difficult-to-treat sarcoma subtype affecting predominantly male adolescents. Extensive intraperitoneal seeding is common and requires multimodal management. With no standard therapy established, the prognosis remains poor, and new treatment options are needed.

Safety and Efficacy of [Lu]-PSMA-I&T Radioligand Therapy in Octogenarians with Metastatic Castration-Resistant Prostate Cancer: Report on 80 Patients over the Age of 80 Years.

Lu-labeled prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a new treatment option for metastatic castration-resistant prostate cancer (mCRPC). Its low toxicity profile favors use in elderly patients or in patients with critical comorbidities. The purpose of this analysis was to evaluate the efficacy and safety of [Lu]-PSMA RLT in mCRPC patients at least 80 y old.

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.

[Procedure Guideline for Prostate Cancer Imaging with PSMA-ligand PET/CT].

PSMA-PET/CT for imaging prostate cancer (PC) has spread worldwide since its clinical introduction in 2011. The majority of experiences have been collected for PSMA-PET-imaging of recurrent PC. Data for primary staging of high-risk PC are highly promising.

Synthesis and preclinical evaluation of novel Tc-labeled PSMA ligands for radioguided surgery of prostate cancer.

Background: Radioguided surgery (RGS) has recently emerged as a valuable new tool in the management of recurrent prostate cancer (PCa). After preoperative injection of a Tc-labeled prostate-specific membrane antigen (PSMA) inhibitor, radioguided intraoperative identification and resection of lesions is facilitated by means of suitable γ-probes. First clinical experiences show the feasibility of RGS and suggest superiority over conventional lymph node dissection in recurrent PCa.

PSMA PET/CT: joint EANM procedure guideline/SNMMI procedure standard for prostate cancer imaging 2.0.

Here we aim to provide updated guidance and standards for the indication, acquisition, and interpretation of PSMA PET/CT for prostate cancer imaging. Procedures and characteristics are reported for a variety of available PSMA small radioligands. Different scenarios for the clinical use of PSMA-ligand PET/CT are discussed.

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.

Reduced splenic uptake on Ga-Pentixafor-PET/CT imaging in multiple myeloma - a potential imaging biomarker for disease prognosis.

Beyond being a key factor for tumor growth and metastasis in human cancer, C-X-C motif chemokine receptor 4 (CXCR4) is also highly expressed by a number of immune cells, allowing for non-invasive read-out of inflammatory activity. With two recent studies reporting on prognostic implications of the spleen signal in diffusion-weighted magnetic resonance imaging in patients with plasma cell dyscrasias, the aim of this study was to correlate splenic Ga-Pentixafor uptake in multiple myeloma (MM) with clinical parameters and to evaluate its prognostic impact. Eighty-seven MM patients underwent molecular imaging with Ga-Pentixafor-PET/CT.

Diverse PSMA expression in primary prostate cancer: reason for negative [Ga]Ga-PSMA PET/CT scans? Immunohistochemical validation in 40 surgical specimens.

Purpose: The purpose of this study was to immunohistochemically validate the primary tumor PSMA expression in prostate cancer (PCa) patients imaged with [Ga]Ga-PSMA PET/CT prior to surgery, with special consideration of PET-negative cases.

Methods: The study included 40 men with newly diagnosed treatment-naïve PCa imaged with [Ga]Ga-PSMA I&T PET/CT as part of the diagnostic work-up prior to radical prostatectomy. All primary tumors were routinely stained with H&E.

Validation of F-rhPSMA-7 and F-rhPSMA-7.3 PET Imaging Results with Histopathology from Salvage Surgery in Patients with Biochemical Recurrence of Prostate Cancer.

F-rhPSMA-7, and its single diastereoisomer form, F-rhPSMA-7.3, are prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals. Here, we investigated their accuracy for the assessment of lymph node (LN) metastases validated by histopathology.

F-rhPSMA-7 PET for the Detection of Biochemical Recurrence of Prostate Cancer After Curative-Intent Radiation Therapy: A Bicentric Retrospective Study.

This bicentric, retrospective analysis investigated the efficacy of PET/CT with a novel theranostic prostate-specific membrane antigen (PSMA)--targeting ligand, F-rhPSMA-7, in patients with biochemical recurrence (BCR) of prostate cancer after curative-intent primary radiotherapy. Datasets from patients with BCR of prostate cancer after external-beam radiation therapy or brachytherapy who underwent F-rhPSMA-7 PET/CT at either Technical University Munich or Ludwig-Maximilians-University Munich were retrospectively reviewed by experienced nuclear medicine physicians and radiologists at both centers. The median injected activity was 299 MBq (range, 204-420 MBq), and the median uptake time was 77 min (range, 46-120 min).

Imaging of C-X-C Motif Chemokine Receptor 4 Expression in 690 Patients with Solid or Hematologic Neoplasms Using Ga-Pentixafor PET.

In recent years, molecular imaging addressing the C-X-C motif chemokine receptor 4 (CXCR4) has increasingly been used in various clinical settings. Here, we aimed to assess radiopharmaceutical uptake and image contrast to determine the most relevant clinical applications for CXCR4-directed imaging. We also investigated the impact of specific activity on scan contrast.

Preclinical biodistribution and dosimetry and human biodistribution comparing F-rhPSMA-7 and single isomer F-rhPSMA-7.3.

Background: Radiohybrid prostate-specific membrane antigen (rhPSMA) ligands such as F-rhPSMA-7 are a new class of theranostic agents in clinical development for prostate cancer. We compared preclinical dosimetry and human biodistribution of F-rhPSMA-7 with that of single diastereoisomer form, F-rhPSMA-7.3.