Synthesis and evaluation of [F]cinacalcet for the imaging of parathyroid hyperplasia.

Introduction: Parathyroid hyperplasia is a disease characterized by overactive parathyroid glands secreting increased levels of parathyroid hormone. Surgical removal of the parathyroid glands is the standard treatment but requires precise pre-operative localization of the glands. However, currently available imaging modalities show limited sensitivity.

Evaluating N-difluoromethyltriazolium triflate as a precursor for the synthesis of high molar activity [ F]fluoroform.

The trifluoromethyl group is a prominent motif in biologically active compounds and therefore of great interest for the labeling with the positron emitter fluorine-18 for positron emission tomography (PET) imaging. Multiple labeling strategies have been explored in the past; however, most of them suffer from low molar activity due to precursor degradation. In this study, the potential of 1-(difluoromethyl)-3-methyl-4-phenyl-1H-1,2,3-triazol-3-ium triflate as precursor for the synthesis of the [ F]trifluoromethylation building block [ F]fluoroform with high molar activity was investigated.

Fluorine-18 labelled Ruppert-Prakash reagent ([F]MeSiCF) for the synthesis of F-trifluoromethylated compounds.

This article describes the first synthesis and application of fluorine-18 labelled Ruppert-Prakash reagent [18F]Me3SiCF3. [18F]Me3SiCF3 was synthesized from [18F]fluoroform with radiochemical yields of 85-95% and radiochemical purities of >95% within 20 minutes. 18F-trifluoromethylated compounds were successfully prepared by reaction of [18F]Me3SiCF3 with benzaldehydes, acetophenones and benzophenones.

Fully Automated Zr Labeling and Purification of Antibodies.

Dozens of monoclonal antibodies (mAbs) have been approved for clinical use, and hundreds more are under development. To support these developments and facilitate a personalized medicine approach, PET imaging and quantification of mAbs, after chelation with desferrioxamine B (DFO) and radiolabeling with Zr, has become attractive. Also, the use of Zr-mAbs in preclinical and clinical studies is expanding rapidly.

Nanobodies targeting the hepatocyte growth factor: potential new drugs for molecular cancer therapy.

Hepatocyte growth factor (HGF) and its receptor c-Met are associated with increased aggressiveness of tumors and poor prognostic outcome of patients with cancer. Here, we report the development and characterization of therapeutic anti-HGF (αHGF)-Nanobodies and their potential for positron emission tomographic (PET) imaging to assess HGF expression in vivo. Two αHGF-Nanobodies designated 1E2 and 6E10 were identified, characterized, and molecularly fused to an albumin-binding Nanobody unit (Alb8) to obtain serum half-life extension.

Biodistribution, radiation dosimetry and scouting of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin's lymphoma using 89Zr-ibritumomab tiuxetan and PET.

Purpose: Positron emission tomography (PET) with (89)Zr-ibritumomab tiuxetan can be used to monitor biodistribution of (90)Y-ibritumomab tiuxetan as shown in mice. The aim of this study was to assess biodistribution and radiation dosimetry of (90)Y-ibritumomab tiuxetan in humans on the basis of (89)Zr-ibritumomab tiuxetan imaging, to evaluate whether co-injection of a therapeutic amount of (90)Y-ibritumomab tiuxetan influences biodistribution of (89)Zr-ibritumomab tiuxetan and whether pre-therapy scout scans with (89)Zr-ibritumomab tiuxetan can be used to predict biodistribution of (90)Y-ibritumomab tiuxetan and the dose-limiting organ during therapy.

Methods: Seven patients with relapsed B-cell non-Hodgkin's lymphoma scheduled for autologous stem cell transplantation underwent PET scans at 1, 72 and 144 h after injection of ~70 MBq (89)Zr-ibritumomab tiuxetan and again 2 weeks later after co-injection of 15 MBq/kg or 30 MBq/kg (90)Y-ibritumomab tiuxetan.

A biparatopic anti-EGFR nanobody efficiently inhibits solid tumour growth.

The epidermal growth factor receptor (EGFR) has been shown to be a valid cancer target for antibody-based therapy. At present, several anti-EGFR monoclonal antibodies have been successfully used, such as cetuximab and matuzumab. X-ray crystallography data show that these antibodies bind to different epitopes on the ecto-domain of EGFR, providing a rationale for the combined use of these two antibody specificities.

Facile labelling of an anti-epidermal growth factor receptor Nanobody with 68Ga via a novel bifunctional desferal chelate for immuno-PET.

Purpose: The ∼15 kDa variable domains of camelid heavy-chain-only antibodies (called Nanobodies®) have the flexibility to be formatted as monovalent, monospecific, multivalent or multispecific single chain proteins with either fast or slow pharmacokinetics. We report the evaluation of the fast kinetic anti-epidermal growth factor receptor (EGFR) Nanobody 7D12, labelled with (68)Ga via the novel bifunctional chelate (BFC) p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS). Df-Bz-NCS has recently been introduced as the chelate of choice for (89)Zr immuno-positron emission tomography (PET).

Immuno-positron emission tomography: shedding light on clinical antibody therapy.

Summation Monoclonal antibodies (mAbs) have been approved for therapeutic use in a broad range of medical indications, especially in oncology, and are forming the most rapidly expanding category of pharmaceuticals. Although engineered mAb fragments and nontraditional antibody-like scaffolds are receiving increasingly more attention, most of the mAb candidates evaluated in past and ongoing clinical trials are full-length mAbs. Immuno-positron emission tomography (PET), the tracking and quantification of mAbs with PET in vivo at superior imaging quality, is an exciting novel option for better understanding the in vivo behavior and efficacy of mAbs in individual patients.

Conjugation and radiolabeling of monoclonal antibodies with zirconium-89 for PET imaging using the bifunctional chelate p-isothiocyanatobenzyl-desferrioxamine.

The positron emitter zirconium-89 ((89)Zr) has very attractive properties for positron emission tomography (PET) imaging of intact monoclonal antibodies (mAbs) using immuno-PET. This protocol describes the step-by-step procedure for the facile radiolabeling of mAbs or other proteins with (89)Zr using p-isothiocyanatobenzyl-desferrioxamine (Df-Bz-NCS). First, Df-Bz-NCS is coupled to the lysine-NH(2) groups of a mAb at pH 9.

p-Isothiocyanatobenzyl-desferrioxamine: a new bifunctional chelate for facile radiolabeling of monoclonal antibodies with zirconium-89 for immuno-PET imaging.

Purpose: Immuno-PET is an emerging imaging tool for the selection of high potential antibodies (mAbs) for imaging and therapy. The positron emitter zirconium-89 ((89)Zr) has attractive characteristics for immuno-PET with intact mAbs. Previously, we have described a multi-step procedure for stable coupling of (89)Zr to mAbs via the bifunctional chelate (BFC) tetrafluorophenol-N-succinyldesferal (TFP-N-sucDf).

Quantitative PET imaging of Met-expressing human cancer xenografts with 89Zr-labelled monoclonal antibody DN30.

Purpose: Targeting the c-Met receptor with monoclonal antibodies (MAbs) is an appealing approach for cancer diagnosis and treatment because this receptor plays a prominent role in tumour invasion and metastasis. Positron emission tomography (PET) might be a powerful tool for guidance of therapy with anti-Met MAbs like the recently described MAb DN30 because it allows accurate quantitative imaging of tumour targeting (immuno-PET). We considered the potential of PET with either (89)Zr-labelled (residualising radionuclide) or (124)I-labelled (non-residualising radionuclide) DN30 for imaging of Met-expressing tumours.

Preparation and evaluation of (89)Zr-Zevalin for monitoring of (90)Y-Zevalin biodistribution with positron emission tomography.

Purpose: To evaluate whether (89)Zr can be used as a PET surrogate label for quantification of (90)Y-ibritumomab tiuxetan ((90)Y-Zevalin) biodistribution and dosimetry before myeloablative radioimmunotherapy.

Methods: Zevalin was labelled with (89)Zr by introducing N-succinyldesferal (N-sucDf) as a second chelate. For comparison of the in vitro stability of (89)Zr-Zevalin and (88)Y-Zevalin (as a substitute for (90)Y), samples were incubated in human serum at 37 degrees C up to 6 days.

Performance of immuno-positron emission tomography with zirconium-89-labeled chimeric monoclonal antibody U36 in the detection of lymph node metastases in head and neck cancer patients.

Purpose: Immuno-positron emission tomography (PET), the combination of PET with monoclonal antibodies (mAb), is an attractive option to improve tumor detection and to guide mAb-based therapy. The long-lived positron emitter zirconium-89 ((89)Zr) has ideal physical characteristics for immuno-PET with intact mAbs but has never been used in a clinical setting. In the present feasibility study, we aimed to evaluate the diagnostic imaging performance of immuno-PET with (89)Zr-labeled-chimeric mAb (cmAb) U36 in patients with squamous cell carcinoma of the head and neck (HNSCC), who were at high risk of having neck lymph node metastases.

(89)Zr as a PET surrogate radioisotope for scouting biodistribution of the therapeutic radiometals (90)Y and (177)Lu in tumor-bearing nude mice after coupling to the internalizing antibody cetuximab.

Unlabelled: Immuno-PET as a scouting procedure before radioimmunotherapy (RIT) aims at confirming tumor targeting and accurately estimating radiation dose delivery to both tumor and normal tissues and might therefore be of value for selection of patient candidates for RIT. A prerequisite for this approach is that PET radioimmunoconjugates and RIT radioimmunoconjugates must show a similar biodistribution. In the present study, we evaluated the potential of the long-lived positron emitter (89)Zr to predict biodistribution of the residualizing therapeutic radiometals (88)Y (as a substitute for (90)Y) and (177)Lu when labeled to the monoclonal antibody (mAb) cetuximab via different types of chelates.

High-quality 124I-labelled monoclonal antibodies for use as PET scouting agents prior to 131I-radioimmunotherapy.

Purpose: Monoclonal antibodies (MAbs) labelled with 124I are an attractive option for quantitative imaging with positron emission tomography (PET) in a scouting procedure prior to 131I-radioimmunotherapy (131I-RIT). In this study, three important items in the labelling of MAbs with 124I were introduced to obtain optimal and reproducible product quality: restoration of radiation-induced inorganic deterioration of the starting 124I solution, radiation protection during and after 124I labelling, and synchronisation of the I/MAb molar ratio.

Methods: A new method was applied, using an NaIO3/NaI carrier mix, realising in one step >90% restoration of deteriorated 124I into the iodide form and chemical control over the I/MAb molar ratio.

Long-lived positron emitters zirconium-89 and iodine-124 for scouting of therapeutic radioimmunoconjugates with PET.

Antibody-PET imaging might be of value for the selection of radioimmunotherapy (RIT) candidates to confirm tumor targeting and to estimate radiation doses to tumor and normal tissues. One of the requirements to be set for such a scouting procedure is that the biodistributions of the diagnostic and therapeutic radioimmunoconjugates should be similar. In the present study we evaluated the potential of the positron emitters zirconium-89 ((89)Zr) and iodine-124 ((124)I) for this approach, as these radionuclides have a relatively long half-life that matches with the kinetics of MAbs in vivo (t(1/2) 3.

Discordance of genetic alterations between primary head and neck tumors and corresponding metastases associated with mutational status of the TP53 gene.

Ample molecular data are available on the progression from normal mucosa to invasive head and neck squamous cell carcinoma (HNSCC), but information on further genetic progression to metastatic disease is scarce. To obtain insight into the metastatic process, we compared 23 primary HNSCCs with 25 corresponding lymph node metastases (LNMs) and 10 corresponding distant metastases (DMs) with respect to TP53 mutations and patterns of loss of heterozygosity (LOH) based on 26 microsatellite markers on six chromosome arms (3p, 9p, 17p, 13q, 8p, and 18q). In 18 of the 23 patients, a TP53 mutation was detected in the primary tumor, and in all cases the same TP53 mutation was present in the corresponding LNM or DM.