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

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. Received 22 September and in revised form 2 November 1999     

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

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.     

Enantioselective synthesis of no-carrier-added (NCA) 6-[18F]fluoro-L-DOPA.

The application of a chiral phase-transfer-catalyst (PTC) in the synthesis of N.C.A. 6-[18F]fluoro-L-DOPA has been recently developed. The 6-trimethylammoniumveratraldehyde triflate precursor and PTC (O-allyl-N-(9)-anthracenylcinchonidinium bromide) were synthesized and successful synthesis route was developed for the preparation of 6-[18F]fluoro-L-DOPA with high radiochemical yields (4-9%, decay uncorrected) and short synthesis time (80min). The radiochemical purity was over 99% and no D-isomer was detected by HPLC analysis using a chiral mobile phase.     

The synthesis of [36Cl]-, [82Br]- and [123I]-labelled 1-(3'-chloro-(bromo and iodo)-3'-deoxy-beta-D-arabinofuranosyl)uracil

Reaction of the epoxy nucleoside 1-(2',3'-epoxy-beta-D-lyxofuranosyl)uracil (1) with [36Cl]HCl afforded [36Cl]-1-(3'-chloro-3'-deoxy-beta-D-arabinofuranosyl)uracil (2a) with a specific activity of 5.48 MBq mmol-1. A similar reaction of 1 with [82Br]NH4Br yielded [82Br]-1-(3'-bromo-3'-deoxy-beta-D-arabinofuranosyl)uracil (2b) with a specific activity of 29 MBq mmol-1. Alternatively neutron activation of the preformed [81Br]-1-(3'-bromo-3'-deoxy-beta-D-arabinofuranosyl)uracil (2b) gave low yields of the [82Br)-labelled 2b with a specific activity of 8.99 MBq mmol-1. [123I]-1-(3'-Iodo-3'-deoxy-beta-D-arabinofuranosyl)uracil (2c) was similarly prepared with a specific activity of 125 GBq mmol-1 by the reaction of [123I]HI with the epoxide. These compounds were prepared for evaluation as non-invasive tumor imaging radiopharmaceuticals.     

Preparation of 15-(p-[123I]iodophenyl) pentadecanoic acid and 15-(p-[123I]iodophenyl)-3-methylpentadecanoic acid by means of Sn

A procedure for labelling 15-(p-iodophenyl) pentadecanoic acid (IPPA) and 15-(p-iodophenyl)-3-methylpentadecanoic acid (3-IPMPA) with ¹²³I, using Sn in an acetic acid medium, is described. The method results in an overall radiochemical yield of more than 96%, obtained in a total reaction time of 45 min. Quality control of the radiopharmaceuticals is performed by means of HPLC.     

Comparative biodistribution study of the new tumor tracer [123I]-2-iodo-L-phenylalanine with [123I]-2-iodo-L-tyrosine

INTRODUCTION: Both A- and l-type amino acid transport are increased in tumor cells relative to normal tissue; these transport systems have been the major focus of the development of amino acid tumor tracers to overcome the limitations of [(18)F]-fluorodeoxyglucose ((18)F-FDG). The newly developed tracer 2-amino-3-(2-[(123)I]iodophenyl)propanoic acid ([(123)I]-2-iodo-l-phenylalanine) showed high and specific tumor uptake, slow renal elimination and low brain uptake. We compared [(123)I]-2-iodo-L-phenylalanine with 2-amino-3-(4-hydroxy-2-[(123)I]iodophenyl)propanoic acid ([(123)I]-2-iodo-L-tyrosine), an L-tyrosine analogue that has recently entered clinical trials. METHODS: [(123)I]-2-iodo-L-phenylalanine and [(123)I]-2-iodo-L-tyrosine were evaluated in rhabdomyosarcoma tumor-bearing athymic mice by means of dynamic planar imaging (DPI) and dissection. A displacement study with L-phenylalanine was performed to prove the specificity of tracer tumor uptake, and kinetic modeling was applied to the DPI results. Moreover, the biodistribution of both tracers was compared with that of (18)F-FDG. RESULTS: Both [(123)I]-2-iodo-L-phenylalanine and [(123)I]-2-iodo-L-tyrosine showed fast, high and specific tumor accumulation with no significant difference. However, [(123)I]-2-iodo-L-phenylalanine was cleared faster from the blood to the bladder in comparison with the tyrosine analogue. Moreover, [(123)I]-2-iodo-L-phenylalanine tumor uptake equilibrated faster with blood. Dissection showed that [(123)I]-2-iodo-L-tyrosine slightly accumulated in the liver, which was not the case for the phenylalanine analogue. In contrast to (18)F-FDG, both tracers showed low uptake in the heart and normal brain tissue, which is advantageous for tumor detection in these organs. CONCLUSIONS: [(123)I]-2-iodo-L-phenylalanine showed more promising characteristics for oncological imaging as compared with [(123)I]-2-iodo-L-tyrosine. The former tracer not only demonstrated faster blood clearance but also showed that the tracer uptake in the tumor reached its equilibrium with the blood pool activity faster, which led to faster and better tumor contrast. Moreover, both tracers could overcome an important limitation of (18)F-FDG-its high normal brain uptake.     

A rapid and efficient preparation of [123I]radiopharmaceuticals using a small HPLC (Rocket) column.

A simplified method for the rapid and efficient preparation of [(123)I]radiopharmaceuticals is described. Three radiopharmaceuticals, [(123)I]beta-CIT, [(123)I]MIBG and [(123)I]clioquinol, were synthesised and purified as model compounds. The radiotracers were labelled with iodine-123 using electrophilic oxidative conditions and purified by a compact semi-preparative reverse phase column (C-18, 3 microm, 7 x 53 mm, Alltima Rocket, Alltech) using aqueous-ethanol as HPLC solvents that were directly used for radiopharmaceutical formulation. The radiochemical purity of the radioiodinated tracers as assessed by analytical HPLC was higher than 99% with specific activity higher than 3 GBq/nmol. The total preparation time of a radiotracer ranged from 40 to 60 min and, starting from 3.7 GBq of iodine-123, more than 2.5 GBq of formulated radiopharmaceuticals were available for clinical investigations.     

Enzymatic synthesis of no-carrier-added 6-[18F]fluoro-L-dopa with beta-tyrosinase.

An enzymatic synthesis of nca 6-[18F]fluoro-L-dopa has been developed. The process consists of a chemical synthesis of 4-[18F]fluorocatechol and its enzymatic reaction with beta-tyrosinase. The 4-[18F]fluorocatechol was prepared by nucleophilic aromatic substitution of the NO2 group on 6-nitroveratoraldehyde with [K/222]+18F-, followed by decarbonylation with tris(triphenylphosphine) rhodium(I) chloride and hydrolysis with hydroiodic acid. By C18 Sep-Pak purification, 4-[18F]fluorocatechol was obtained in ethanol with a radiochemical yield of 9.2%. An enzymatic reaction of 4-[18F]fluorocatechol, ammonium and pyruvate catalyzed by beta-tyrosinase in an ethanolic Tris-HCl buffer (pH 9.0) containing ascorbate gave within 5 min 6-[18F]fluoro-L-dopa with an approximate radiochemical yield of 60% without any isomers. The deproteinized reaction mixture was applied to a preparative reverse phase column, and the radiochemically and enantiomerically pure 6-[18F]fluoro-L-dopa was obtained with a radiochemical yield of 2.0% based on [18F]F- (decay-corrected). The synthesis time was 150 min from the EOB and the specific activity was > 200 GBq/micromol.     

Pulmonary inhalation scintigraphy using N-isopropyl-p-[123I]iodoamphetamine (123I-IMP) aerosol

N-isopropyl-p-[123I]iodoamphetamine (123I-IMP) is lipophilic substance and permeates through the alveolar epithelium via intracellular transport, whereas 99mTc-DTPA is water-soluble substance and permeates through the alveolar epithelium via paracellular transport. We performed inhalation lung imaging using 123I-IMP and 99mTc-DTPA in order to assess alveolar epithelial permeability in 4 patients with restrictive ventilatory impairment, and 5 volunteers including one smoker. The time-activity (T/A) curves of 123I-IMP were well fitted into two compartments, first and slow, by least-squares fit technique, in contrast to 99mTc-DTPA fitted well with one compartment. In 4 normal volunteers, the T/A curves of the lower pulmonary fields declined faster than those of other pulmonary fields. In 99mTc-DTPA studies, the Kep values of patients with restrictive ventilatory impairment (n = 4) were higher than those of normal volunteers (n = 4) (2.14 +/- 0.30 x 10(-4) vs 1.48 +/- 0.41 x 10(-4), p less than 0.005). On the other hand, in 123I-IMP studies, the Kep values of the patients were much lower than those of normal volunteers (6.79 +/- 0.55 x 10(-5) vs 1.52 +/- 0.45 x 10(-3), p less than 0.005).     

Characterization of 3-[123I]iodo-L-alpha-methyl tyrosine ([123I]IMT) transport into human Ewing's sarcoma cells in vitro

3-[(123)I]Iodo-L-alpha-methyl tyrosine ([(123)I]IMT) scintigraphy of extracranial malignant tumors has been described, but little is known about the transport systems involved in [(123)I]IMT uptake into extracranial tumor cells. Here, the precise kinetics of [(123)I]IMT transport into human Ewing's sarcoma cells (VH-64) was determined. The apparent Michaelis constant was of high affinity value (K(m)=41.7+/-3.9 microM) and maximum transport velocitiy amounted to V(max)=20.7+/-0.6 nmol x mg protein(-1) x 10 min(-1). Inhibition experiments revealed the predominance of [(123)I]IMT uptake via sodium-independent system L.     

An automated synthesis module for preparation of L-3-[123I]iodo-alpha-methyl tyrosine.

L-3-[123I]iodo-alpha-methyl tyrosine (IMT) is an artificial amino acid suitable for SPECT imaging of various tumours. Manual synthesis of this radiopharmaceutical is reliable, but time-consuming and may require handling of large quantities of radioactivity. We developed an automated IMT synthesis module, which prepares a ready-to-inject product that meets radiopharmaceutical requirements and is identical to the manually synthesised equivalent. Current advantages include decreased operator assistance time and reduced radiation exposure. Application may be extended to other radiopharmaceuticals, including high-dose preparations for therapeutic use.     

[123I]Iodoamphetamine SPECT imaging

SPECT imaging of [¹²³I]IMP is reviewed. Methods for radiopharmaceutical production are discussed with an emphasis on labeling small quantities of IMP. Limited angle tomography and full angle SPECT with standard cameras and special imaging systems are reviewed. Selection of collimator and methods of reconstruction are discussed. Clinical studies are described with emphasis on stroke, epilepsy and dementia. The efforts to perform quantitative imaging of rCBF with [¹²³I]IMP are reviewed.     

Improved synthesis of no-carrier-added p-[124I]iodo-L-phenylalanine and p-[131I]iodo-L-phenylalanine for nuclear medicine applications in malignant gliomas.

This work describes the synthesis and the tumor affinity testing of no-carrier-added (n.c.a.) p-[(124)I]iodo-L-phenyalanine ([(124)I]IPA) and n.c.a. p-[(131)I]iodo-l-phenyalanine ([(131)I]IPA) as radiopharmaceuticals for imaging brain tumors with PET and for radionuclid-based therapy, respectively. Parameters for labeling were optimized with regard to the amount of precursor, temperature and time. Thereafter, n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA were investigated in rat F98 glioma and in primary human A1207 and HOM-T3868 glioblastoma cells in vitro, followed by an in vivo evaluation in CD1 nu/nu mice engrafted with human glioblastoma. No-carrier-added [(124)I]IPA and n.c.a. [(131)I]IPA were obtained in 90+/-6% radiochemical yield and >99% radiochemical purity by iododestannylation of N-Boc-4-(tri-n-butylstannyl)-L-phenylalanine methylester in the presence of chloramine-T, followed by hydrolysis of the protecting groups. The total synthesis time, including the HPLC separation and pharmacological formulation, was less than 60 min and compatible with a clinical routine production. Both amino acid tracers accumulated intensively in rat and in human glioma cells. The radioactivity incorporation in tumor cells following a 15-min incubation at 37 degrees C/pH 7.4 varied from 25% to 42% of the total loaded activity per 10(6) tumor cells (296-540 cpm/1000 cells). Inhibition experiments confirmed that n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA were taken up into tumor by the sodium-independent L- and ASC-type transporters. Biodistribution and whole-body imaging by a gamma-camera and a PET scanner demonstrated a high targeting level and a prolonged retention of n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA within the xenotransplanted human glioblastoma and a primarily renal excretion. However, an accurate delineation of the tumors in mice was not possible by our imaging systems. Radioactivity accumulation in the thyroid and in the stomach as a secondary indication of deiodination was less than 1% of the injected dose at 24h p.i., confirming the high in vivo stability of the radiopharmaceuticals. In conclusion, n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA are new promising radiopharmaceuticals, which can now be prepared in high radiochemical yields and high purity for widespread clinical applications. The specific and high-level targeting of n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA to glioma cells in vitro and to glioblastoma engrafts in vivo encourages further in vivo validations to ascertain their clinical potential as agent for imaging and quantitation of gliomas with PET, and for radionuclid-based therapy, respectively.     

Myocardial uptake of meta-[123I]-iodobenzylguanidine [( 123I]-MIBG) in patients with myocardial infarct

Meta-123I-iodobenzylguanidine (123I-MIBG), which is an analog of norepinephrine, can be used to evaluate the integrity and function of sympathetic nerve endings in the heart. Myocardial uptake of 123I-MIBG was studied in 30 myocardial infarction patients and compared with the distribution of blood flow assessed with 201Tl. It was found that when a cold defect appeared on the 201Tl scintigram, its localization was identical to the cold defect on the 123I-MIBG scintigram. On the other hand, in three cases, a defect was found on the 123I-MIBG scintigram, corresponding to the electrocardiographic localization of the infarct, whereas the 201Tl scintigram was normal. Most strikingly, the present study shows that drugs (antagonists of the adrenergic receptors, calcium antagonists, amiodarone) decrease or even abolish (as in the case of labetalol) myocardial uptake of 123I-MIBG. Consequently, any interpretation of the 123I-MIBG scintigram must take into account the treatment administered.     

Synthesis of [6-36Cl]chlorouracil, [6-82Br]bromouracil and [6-123I]iodouracil

Three C-6 radiohalogenated uracil derivatives were prepared by non-isotopic halogen exchange reactions for evaluation as diagnostic radiopharmaceuticals. [6-³⁶Cl]chlorouracil (radiochemical yield 77%, specific activity 5.66 MBq mmol⁻¹) was prepared via calcium [³⁶Cl]chloride exchange on 6-iodouracil, [6-⁸²Br]bromouracil (27%, 68.4 MBq mmol⁻¹) was prepared via ammonium [⁸²Br]bromide exchange on 6-iodouracil and [6-¹²³I]iodouracil (55.4%, 5.41 GBq mmol⁻¹) was prepared via sodium [¹²³I]iodide exchange on 6-chlorouracil. The specific activities and radiochemical yields were dependent upon the halide-ion concentration.     

Myocardial uptake of meta-[123I]-iodobenzylguanidine ([123I]-MIBG) in patients with myocardial infarct

Meta-¹²³I-iodobenzylguanidine (¹²³I-MIBG), which is an analog of norepinephine, can be used to evaluate the integrity and function of sympathetic nerve endings in the heart. Myocardial uptake of ¹²³I-MIBG was studied in 30 myocardial infarction patients and compared with the distribution of blood flow assessed with ²⁰¹Tl. It was found that when a cold defect appeared on the ²⁰¹Tl scintigram, its localization was identical to the cold defect on the ¹²³I-MIBG scintigram. On the other hand, in three cases, a defect was found on the ¹²³I-MIBG scintigram, corresponding to the electrocardiographic localization of the infarct, whereas the ²⁰¹Tl scintigram was normal. Most strikingly, the present study shows that drugs (antagonists of the adrenergic receptors, calcium antagonists, amiodarone) decrease or even abolish (as in the case of labetalol) myocardial uptake of ¹²³I-MIBG. Consequently, any interpretation of the ¹²³I-MIBG scintigram must take into account the treatment administered.