Radiosynthesis of SPECT tracers via a copper mediated 123I iodination of (hetero)aryl boron reagents.

Preparation and investigation of tumor affinity, uptake kinetic and transport mechanism of iodine-123-labelled amino acid derivatives in human pancreatic carcinoma and glioblastoma cells

Radiolabelled (bio)molecules have advanced many areas of science from fundamental biology to human health including applications in molecular imaging and more generally nuclear medicine. Today, the field of radiochemistry is rapidly expanding, a trend resulting from the increasing demand for labelled molecules necessary for diagnosis and to accelerate pharmaceutical drug development. More often, the synthesis of labelled (bio)molecules employs a pre-functionalised precursor to allow for the chemoselective installation of a particular radioisotope-containing substituent. Among the array of precursors available, boron reagents occupy a prominent place because they are easy to handle, numerous possibilities exist for their preparation, and their reactivity has been well studied especially in cross-coupling chemistry. In this review, we discuss the value of boron-based precursors for the radiolabelling of (bio)molecules with the radionuclides carbon-11, fluorine-18, iodine-123, iodine-125 and iodine-131, and we illustrate how these radiosynthetic advances have opened the radiochemical space available for areas such as PET and SPECT imaging.

/pdf/boron-reagents-for-divergent-radiochemistry-ohm8r65zoc.pdf

Boron reagents for divergent radiochemistry

In developing iodine-123-labelled amino acid derivatives for imaging cerebral gliomas by single-photon emission tomography (SPET), we compared p-[123I]iodo-L-phenylalanine (IPA), L-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid (ITIC) and L-3-[123I]iodo-alpha-methyltyrosine (IMT) with regard to their uptake in human glioblastoma T99 and T3868 cells, and thereafter studied the mechanisms promoting the cellular uptake. The potential of the 123I-iodinated agents for use as SPET radiopharmaceuticals was evaluated in healthy experimental rats as well as in rats with stereotactically implanted C6 gliomas. The radiopharmaceutical uptake into glioblastoma cells was rapid, temperature and pH dependent, and linear during the first 5 min. Equilibrium was reached after 15-20 min, except in the case of ITIC, the initial uptake of which gradually decreased from 15 min onwards. The radioactivity concentration in glioma cells following 30-min incubation at 37 degrees C (pH 7.4) varied from 11% to 35% of the total activity per million cells (ITIC < IMT < or = IPA). Competitive inhibition experiments using alpha-(methylamino)-isobutyric acid and 2-amino-2-norbornane-carboxylic acid, known as specific substrates for systems A and L, respectively, as well as representative amino acids preferentially transported by system ASC, indicated that IPA, like IMT, is predominantly mediated by the L and ASC transport systems, while no significant involvement of the A transport system could be demonstrated. By contrast, none of the three principal neutral amino acid transport systems (A, L and ASC) appear to be substantially involved in the uptake of ITIC into glioblastoma cells. Analysis of uptake under conditions that change the cell membrane potential, i.e. in high K+ medium, showed that the membrane potential plays an important role in ITIC uptake. Alteration of the mitochondrial activity by means of valinomycin or nigericin induces a slight increase or decrease in the radiopharmaceutical uptake, suggesting a minor contribution of the mitochondria in the uptake. IPA, IMT and ITIC passed the blood-brain barrier, and thereafter showed efflux from the brain. The radioactivity concentration in healthy rat brain 15 min following intravenous injection varied from 0.07% (ITIC) to 0.27% ID/g (IPA). In comparison, the brain uptake in the stereotactically implanted C6 glioma rats was substantially higher (up to 1.10% ID/g 15 min p.i.), with tumour-to-background ratios greater than 4. These data indicate that IPA and ITIC, like IMT, exhibit interesting biological characteristics which hold promise for in vivo brain tumour investigations by SPET.

Investigation of iodine-123-labelled amino acid derivatives for imaging cerebral gliomas: uptake in human glioma cells and evaluation in stereotactically implanted C6 glioma rats

In clinical and research studies, images obtained using carrier-added meta-[123I]iodobenzylguanidine (c.a. [123I]MIBG) have shown quite variable quality, with varying levels of uptake in lung, liver and mediastinum; this is a significant problem for quantification of the myocardial uptake by means of region ratios. First experimental and preliminary human data in respect of no-carrier-added (n.c.a.) [123I]MIBG are indicative of improved imaging quality. The aim of the present study was to evaluate the clinical value of myocardial scintigraphy with n.c.a. [123I]MIBG in patients with tachyarrhythmias. The study population comprised 24 patients with tachyarrhythmogenic diseases routinely studied by cardiac single-photon emission tomography (SPET) with [123I]MIBG. Twelve of the 24 patients were studied with c.a. [123I]MIBG (seven females and five males; mean age 42±13 years, range 20–60 years), whereas the other 12 were studied with n.c.a. [123I]MIBG (ten females, two males; mean age 41±11 years, range 18–60 years, P=NS). For quantification of the specific uptake in the different organs, count ratios were calculated on SPET images acquired 4 h p.i. Visual analysis of all [123I]MIBG scans showed improved image quality (improved contrast between heart and neighbouring organs) in n.c.a. studies as compared with c.a. studies. A significantly higher heart/left atrial blood ratio was found in the n.c.a. studies as compared with the c.a. studies (10.3±3.2 vs 5.3±1.3, P=0.0003); furthermore, significantly higher heart/lung and heart/liver ratios (2.5±0.6 vs 1.5±0.3, P=0.0002, and 0.8±0.2 vs 0.6±0.1, P=0.0006, respectively) were obtained in the c.a. studies, whereas lung/left atrial blood and liver/left atrial blood ratios showed no significant differences (4.2±1.3 vs 3.6±1.1, P=0.39, and 13.7±5.2 vs 9.6±2.2, P=0.21, respectively). In conclusion, the use of n.c.a. [123I]MIBG yields a significantly higher myocardial uptake associated with improvement in contrast between the heart and neighbouring organs and is therefore superior to the commercially available c.a. [123I]MIBG for use in clinical and research studies of the myocardial presynaptic sympathetic nervous system. Furthermore, our data indicate that for quantification the use of a left atrial blood reference region of interest, which is only available on SPET studies, is to be recommended.

Clinical evaluation of no-carrier-added meta-[123I]iodobenzylguanidine for myocardial scintigraphy.

Meta-[123I]iodobenzylguanidine (123I-MIBG) is currently used to assess myocardial sympathetic innervation by single photon emission tomography (SPET). In recent studies, an enhanced cardiac uptake of 123I-MIBG with high specific activity has been reported, suggesting the clinical potential of no-carrier-added (n.c.a.) 123I-MIBG in the assessment of abnormalities in cardiac sympathetic function. This paper describes the preparation of n.c.a. 123I-MIBG by non-isotopic Cu(I)-assisted [123I]iododebromination and by [123I]iododestannylation, both resulting in n.c.a. 123I-MIBG with radiochemical yields of 88 +/- 6% and high specific activity (> or = 6.3 TBq.mumol-1) in a total synthesis time of less than 50 min. The diagnostic potential of n.c.a. 123I-MIBG (> 6.3 TBq.mumol-1) was studied in 13 patients (nine patients with malignant ventricular arrhythmias and four patients suspected of phaeochromocytoma) and compared to commercial 123I-MIBG (approximately 75 MBq.mumol-1) using a dual-headed SPET camera (MULTISPECT II). High specific activity results in higher 123I-MIBG uptake in the heart and in the liver in all patients. The calculated heart-to-lung and heart-to-liver count ratios 4.5 h post-injection increased by 22 +/- 6% and 10 +/- 5% with n.c.a. 123I-MIBG compared to commercial 123I-MIBG respectively. In contrast, no significant correlation between the specific activity of 123I-MIBG and lung uptake could be established in this study. Analysis of radioactivity in blood after the intravenous injection of n.c.a. and commercially available 123I-MIBG showed an initial rapid clearance of radioactivity from blood, followed by a plateau from 60 min onwards. Within the first 24 h, more than 85% of the plasma activity was unchanged 123I-MIBG. The free 123I-iodide concentration determined 24 h post-injection was 2 +/- 1% with commercial 123I-MIBG and 3 +/- 2% with n.c.a. 123I-MIBG. In conclusion, the results of this investigation indicate that n.c.a. 123I-MIBG is a promising clinical tool for imaging myocardial sympathetic dysfunction by SPET. High specific activity n.c.a. 123I-MIBG can now be prepared by simple one-step methods giving high radiochemical yields and high purity suitable for clinical application. This encourages the further clinical validation of n.c.a. 123I-MIBG on a large scale.

Improved labelling of no-carrier-added 123I-MIBG and preliminary clinical evaluation in patients with ventricular arrhythmias.

This randomized clinical trial assesses the ability of high-dose intravenous sodium selenite treatment to reduce postoperative organ dysfunction and mortality in cardiac surgery patients.

Effect of High-Dose Selenium on Postoperative Organ Dysfunction and Mortality in Cardiac Surgery Patients

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Improved labelling of no-carrier-added 123I-MIBG and preliminary clinical evaluation in patients with ventricular arrhythmias.

Effect of High-Dose Selenium on Postoperative Organ Dysfunction and Mortality in Cardiac Surgery Patients