Radiolabeled PSMA Inhibitors.

PSMA has shown to be a promising target for diagnosis and therapy (theranostics) of prostate cancer. We have reviewed developments in the field of radio- and fluorescence-guided surgery and targeted photodynamic therapy as well as multitargeting PSMA inhibitors also addressing albumin, GRPr and integrin αβ. An overview of the regulatory status of PSMA-targeting radiopharmaceuticals in the USA and Europe is also provided.

Highlight selection of radiochemistry and radiopharmacy developments by editorial board.

Background: The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to update the readership on trends in the field of radiopharmaceutical development.

Results: This commentary of highlights has resulted in 21 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Also the first contribution in relation to MRI-agents is included.

Emerging Radionuclides in a Regulatory Framework for Medicinal Products - How Do They Fit?

Recent years have seen the establishment of several radionuclides as medicinal products in particular in the setting of theranostics and PET. [Lu]Lutetium Chloride or [Cu]Copper Chloride have received marketing authorization as radionuclide precursor, [Ga]Gallium Chloride has received regulatory approval in the form of different Ge/Ga generators. This is a formal requirement by the EU directive 2001/83, even though for some of these radionuclide precursors no licensed kit is available that can be combined to obtain a final radiopharmaceuticals, as it is the case for Technetium-99m.

Guideline on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals.

This guideline on current good radiopharmacy practice (cGRPP) for small-scale preparation of radiopharmaceuticals represents the view of the Radiopharmacy Committee of the European Association of Nuclear Medicine (EANM). The guideline is laid out in the format of the EU Good Manufacturing Practice (GMP) guidelines as defined in EudraLex volume 4. It is intended for non-commercial sites such as hospital radiopharmacies, nuclear medicine departments, research PET centres and in general any healthcare establishments.

Automated [F]PSMA-1007 production by a single use cassette-type synthesizer for clinical examination.

Background: [F]PSMA-1007, a positron emission tomography (PET) tracer, specifically targets prostate-specific membrane antigen (PSMA), which is highly expressed in prostate cancer. PSMA-PET is effective especially for regional detection of biochemical recurrence, which significantly affects patient management. Herein, we established and optimized a one-step radiolabeling protocol to separate and purify [F]PSMA-1007 with a CFN-MPS200 synthesizer for clinical application.

Radionuclides: medicinal products or rather starting materials?

The EU directive 2001/83 describes the community code for medicinal products for human use including radiopharmaceuticals. In its current definition, also radionuclide precursors, such as fluorine-18, need to hold a marketing authorization before being placed on the market. The potential of novel radiopharmaceuticals for nuclear medicine is, although encouraged by European legislation and its respective guidance documents, therefore hampered by the regulatory framework.

DNA damage in human whole blood caused by radiopharmaceuticals evaluated by the comet assay.

Radiopharmaceuticals used for diagnosis or therapy induce DNA strand breaks, which may be detectable by single-cell gel electrophoresis (called comet assay). Blood was taken from patients before and at different time points after treatment with radiopharmaceuticals; blood cells were investigated by the comet assay using the percentage of DNA in the tail as the critical parameter. Whereas [225Ac]Ac-prostate-specific membrane antigen (PSMA)-617 alpha therapy showed no difference relative to the blood sample taken before treatment, beta therapy with [177Lu]Lu-PSMA-617 3 h post-injection revealed a small but significant increase in DNA strand breaks.

[Initiation of clinical multicentre studies with local radiotracer production - Regulatory environment and radiopharmaceutical-organisational aspects].

The aim of this paper is to highlight key aspects to be considered from a radiopharmaceutical point of view when performing prospective multicentre clinical trials using short-lived PSMA-PET-radiopharmaceuticals as investigational medicinal product (IMP). Early prospective multicentre clinical trials are playing an increasingly important role in nuclear medicine translational research; in order to be able to establish new PET tracers with a short physical half-life (e. g.

Impact of F-PSMA-1007 Uptake in Prostate Cancer Using Different Peptide Concentrations: Preclinical PET/CT Study on Mice.

PET radioligands with low molar activity (MA) may underestimate the quantity of the target of interest because of competitive binding of the target with unlabeled ligand. The aim of this study was to evaluate the change in the whole-body distribution of F-PSMA-1007 targeting prostate-specific membrane antigen (PSMA) when solutions with different peptide concentrations are used. Mouse xenograft models of LNCaP (PSMA-positive prostate cancer) ( = 18) were prepared and divided into 3 groups according to the peptide concentration injected: a high-MA group (1,013 ± 146 GBq/μmol; = 6), a medium-MA group (100.

Detection Efficacy of F-PSMA-1007 PET/CT in 251 Patients with Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy.

Prostate-specific membrane antigen (PSMA)-targeted PET imaging recently emerged as a new method for the staging and restaging of prostate cancer. Most published studies investigated the diagnostic potential of Ga-labeled PSMA agents that are excreted renally. F-PSMA-1007 is a novel PSMA ligand that has excellent preclinical characteristics and that is only minimally excreted by the urinary tract, a potential advantage for pelvic imaging.

Tracer uptake in mediastinal and paraaortal thoracic lymph nodes as a potential pitfall in image interpretation of PSMA ligand PET/CT.

Purpose: Since the introduction of Ga-PSMA-11 PET/CT for imaging prostate cancer (PC) we have frequently observed mediastinal lymph nodes (LN) showing tracer uptake despite being classified as benign. The aim of this evaluation was to further analyze such LN.

Methods: Two patient groups with biphasic Ga-PSMA-11 PET/CT at 1 h and 3 h p.

Biochemical Recurrence of Prostate Cancer: Initial Results with [F]PSMA-1007 PET/CT.

Biochemical recurrence (BCR) is a concern for prostate cancer patients after local treatment. Ga-labeled prostate-specific membrane antigen (PSMA) ligands have significantly improved prostate cancer imaging. However, several F-labeled ligands that were developed as fluorinated tracers might present advantages.

Intraindividual Comparison of F-PSMA-1007 and F-DCFPyL PET/CT in the Prospective Evaluation of Patients with Newly Diagnosed Prostate Carcinoma: A Pilot Study.

The introduction of F-labeled prostate-specific membrane antigen (PSMA)-targeted PET/CT tracers, first F-DCFPyL (2-(3-{1-carboxy-5-[(6-F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) and more recently F-PSMA-1007 (((31014)-1-(4-((()-4-carboxy-2-(()-4-carboxy-2-(6-F-fluoronicotinamido)butanamido)butanamido)methyl)phenyl)-3-(naphthalen-2-ylmethyl)-1,4,12-trioxo-2,5,11,13-tetraazahexadecane-10,14,16-tricarboxylic acid)), have demonstrated promising results for the diagnostic workup of prostate cancer. This clinical study presents an intraindividual comparison to evaluate tracer-specific characteristics of F-DCFPyL versus F-PSMA-1007. Twelve prostate cancer patients, drug-naïve or before surgery, received similar activities of about 250 MBq of F-DCFPyL and F-PSMA-1007 48 h apart and were imaged 2 h after injection on the same PET/CT scanner using the same reconstruction algorithm.

Carbon ion radiotherapy: impact of tumor differentiation on local control in experimental prostate carcinomas.

Background: To summarize the research activities of the "clinical research group heavy ion therapy", funded by the German Research Foundation (DFG, KFO 214), on the impact of intrinsic tumor characteristics (grading, hypoxia) on local tumor control after carbon (C-) ion- and photon irradiations.

Methods: Three sublines of syngeneic rat prostate tumors (R3327) with various differentiation levels (highly (-H), moderately (-HI) or anaplastic (-AT1), (diameter 10 mm) were irradiated with 1, 2 and 6 fractions of either C-ions or 6 MV photons using increasing dose levels. Primary endpoint was local tumor control at 300 days.

Procedures for the GMP-Compliant Production and Quality Control of [F]PSMA-1007: A Next Generation Radiofluorinated Tracer for the Detection of Prostate Cancer.

Radiolabeled tracers targeting the prostate-specific membrane antigen (PSMA) have become important radiopharmaceuticals for the PET-imaging of prostate cancer. In this connection, we recently developed the fluorine-18-labelled PSMA-ligand [F]PSMA-1007 as the next generation radiofluorinated Glu-ureido PSMA inhibitor after [F]DCFPyL and [F]DCFBC. Since radiosynthesis so far has been suffering from rather poor yields, novel procedures for the automated radiosyntheses of [F]PSMA-1007 have been developed.

Diagnostic performance of Ga-PSMA-11 (HBED-CC) PET/CT in patients with recurrent prostate cancer: evaluation in 1007 patients.

Purpose: Since the clinical introduction of Ga-PSMA-11 PET/CT, this imaging method has rapidly spread and is now regarded as a significant step forward in the diagnosis of recurrent prostate cancer (PCa). The aim of this study was to analyse the influence of several variables with possible influence on PSMA ligand uptake in a large cohort.

Methods: We performed a retrospective analysis of 1007 consecutive patients who were scanned with Ga-PSMA-11 PET/CT (1 h after injection) from January 2014 to January 2017 to detect recurrent disease.

Intraindividual Comparison of F-PSMA-1007 PET/CT, Multiparametric MRI, and Radical Prostatectomy Specimens in Patients with Primary Prostate Cancer: A Retrospective, Proof-of-Concept Study.

Ga-prostate-specific membrane antigen (PSMA)-11 PET/CT represents an advanced method for the staging of primary prostate cancer (PCa) and diagnosis of recurrent or metastatic PCa. However, because of the narrow availability of Ga the development of alternative tracers is of high interest. The objective of this study was to examine the value of the new PET tracer F-PSMA-1007 for the staging of local disease by comparing it with multiparametric MRI (mpMRI) and radical prostatectomy (RP) histopathology.

Preclinical Evaluation of F-PSMA-1007, a New Prostate-Specific Membrane Antigen Ligand for Prostate Cancer Imaging.

In recent years, several radiotracers targeting the prostate-specific membrane antigen (PSMA) have been introduced. Some of them have had a high clinical impact on the treatment of patients with prostate cancer. However, the number of F-labeled tracers addressing PSMA is still limited.

The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions.

Unlabelled: PET imaging with the prostate-specific membrane antigen (PSMA)-targeted radioligand (68)Ga-PSMA-11 is regarded as a significant step forward in the diagnosis of prostate cancer (PCa). More recently, a PSMA ligand was developed that can be labeled with (68)Ga, (111)In, (177)Lu, and (90)Y. This ligand, named PSMA-617, therefore enables both diagnosis and therapy of PCa.

Investigation of epothilone B-induced cell death mechanisms in human epithelial cancer cells -in consideration of combined treatment with ionizing radiation.

Epothilone B was shown to have promising chemo- and radiosensitizing effects on cells, but the mechanisms underlying cell death remain ambiguous. The aim of the study was to examine selected cell death pathways on the basis of FaDu and A549 cells. Western blot analyses were used for investigation of specific apoptotic markers.

Novel Preclinical and Radiopharmaceutical Aspects of [68Ga]Ga-PSMA-HBED-CC: A New PET Tracer for Imaging of Prostate Cancer.

The detection of prostate cancer lesions by PET imaging of the prostate-specific membrane antigen (PSMA) has gained highest clinical impact during the last years. 68Ga-labelled Glu-urea-Lys(Ahx)-HBED-CC ([68Ga]Ga-PSMA-HBED-CC) represents a successful novel PSMA inhibitor radiotracer which has recently demonstrated its suitability in individual first-in-man studies. The radiometal chelator HBED-CC used in this molecule represents a rather rarely used acyclic complexing agent with chemical characteristics favourably influencing the biological functionality of the PSMA inhibitor.

High management impact of Ga-68 DOTATATE (GaTate) PET/CT for imaging neuroendocrine and other somatostatin expressing tumours.

Introduction: Ga-68 DOTATATE (Ga-octreotate, GaTate) positron emission tomography (PET)/CT has multiple advantages compared with conventional and In-111 octreotide imaging for neuroendocrine tumours and other somatostatin-receptor expressing tumours. This study assesses the management impact of incremental diagnostic information obtained from this technique compared with conventional staging.

Methods: Fifty-nine GaTate PET/CT studies were performed over an 18-month period (52 proven or suspected gastro-entero-pancreatic or bronchial neuroendocrine tumours and seven neural crest/mesenchymal tumours).

Preclinical characterization of 18F-D-FPHCys, a new amino acid-based PET tracer.

Purpose: The imaging potential of a new (18)F-labelled methionine derivative, S-(3-[(18)F]fluoropropyl)-D-homocysteine ((18)F-D-FPHCys), and its selectivity for amino acid transporter subtypes were investigated in vitro and by imaging of human tumour xenografts.

Methods: Expression of members of the system L (LAT isoforms 1-4 and 4F2hc) and ASCT (ASCT isoforms 1 and 2) amino acid transporter subclasses were assessed by quantitative real-time PCR in four human tumour models, including A431 squamous cell carcinoma, PC3 prostate cancer, and Colo 205 and HT-29 colorectal cancer lines. The first investigations for the characterization of (18)F-D-FPHCys were in vitro uptake studies by comparing it with [1-(14)C]-L-methionine ((14)C-MET) and in vivo by PET imaging.