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[123I]-N-methyl-4iododexetimide: a radioiodinated ligand for SPECT studies of myocardial muscarinic receptors
(Kyoto University, 1983-10-25) Kassiou, M; Katsifis, A; Lamnrecht, RM; Hicks, RJ
Muscarinic cholinergic receptors (mAChR) mediate a closing in the rate of contraction of the heart and a decrease in the force of contraction, while changes in receptor density occur in various physiological, pharmacological and clinic condition. Altered muscarinic receptor distribution in the heart may be a substrate for cardiac arrhythmias and lead to cardiac arrest. Attempts to image myocardial mAChR involves use of radiotracers such as [11C]MQNB and [11C]MTRB with limited SPECT radiotracers avaliable. Recently [1231]-4-iododexetimide (I123]IDEX), a potent mAChR antagonist was used for in vivo studies of myocardial mAChR but proved unsuccessful due to its high lung uptake.‘ We are reporting the preparation and evaluation of the hydrophilic quarternized derivative: [123I]-N-methyl-4-iododexetimide (I123]MIDEX). The radiosynthesis involves firstly preparation of [123I]lDEX by electophilic iododesilylation using trifluoroacetic acid as solvent and chloramine-T as the oxidising agent as described elsewhere} followed by treatment of [123I]IDEX with excess CH3I (fig 1). The methylation reaction is carried out by dissolving [123I]IDEX (10 mCi) in tributyl phosphate (50 µL), a solvent known to promote formation of quaternary ammonium salts, followed by addition of CH3I (300 µL). The reaction mixture was tightly stoppered and heated at 90°C for 15 minutes. After evaporating the excess CH3I and cooling the mixture, isolation and purification of the radiopharmaceutical was carried out by preperative HPLC. A µ-Bondapak C18 column (300 x 7.8 mm) was used while the UV absorption was measured at 239 nm and radioactivity measured on a Berthold system. The mobile phase consisted of acetonitrile and 0.1M ammonium acetate buffer (45:55 v.v) and a flow rate of 2.5 mL/min. The retention times of [123I]IDEX and [123I]MIDEX were 38 and 26 minutes respectively. Radiochemical yields of 80% were reached while radiochemical and chemical purities assessed by HPLC were 97% and the specific activity of [123I]MIDEX was identical to [123]IDEX >2000 mCi/µmol. Rat biodistribution studies were performed and showed high heart uptake (2.4 %ID/g) 10 minutes after injection with a heart to lung radioactivity concentration ratio (H/L) of 5.1. The H/L ratio decreased rapidly to 2.2 after 30 minutes and reached unity at 60 minutes. No uptake of [123I]MIDEX was observed in the brain. The specificity and stereoselectivity of [123I]MIDEX binding at 10 minutes was demonstrated by coinjecting a cold load of levetimide (LEV 0.15 mg/kg), dexetimide (DEX 0.15 mg/kg) and methyl-quinuclidinyl benzylate (MQNB 1 mg/kg) (fig 2). With DEX and MQNB the heart uptake was reduced to 0.20 and 0.13 %1D/g displacing 92% and 95% of the activity respectively while LEV maintained high heart uptake (2.2 %ID/g). Interestingly, the kidney uptake was 21% ID/g and remained constant over a period of 30 minutes. Preliminary SPECT studies carried out on rabbit and dog will also be described. The carbon-11 methylation of dexetimide will also be mentioned. These results suggest that [mI]MIDEX has the potential of being developed as a SPECT radiotracer for the characterisation of myocardial muscarinic receptors.
Preparation and pharmacological evaluation of a new central muscarinic cholinergic receptor imaging agent [76Br]-4-bromodexetimide
(Kyoto University, 1983-10-25) Kassiou, M; Loc'h, C; Bottlander, MA; Lambrecht, RM; Katsifis, A; Schmid, L; Ottavivani, M; Mazière, M; Mazière , B
Muscarinic cholinergic receptors (mAChR) play an important role in a number of physiological and behavioural responses. The putative role of muscarinic receptors in neurodegenerative disorders such as Alzheimer's disease, Huntington's disease and dementias associated with Parkinson's disease has generated considerable interest for the non invasive mapping of mAChR. Potential muscarinic imaging agents include 11C- and 123I-QNB analogs, 11C-scopolamine and 11C-benztropine while radiolabelled dexetimide derivatives have shown exciting potential. Simpler methods for the preparation of dexetirnide derivatives incorporating. longer lived isotopes suitable forPET studies is required. We are reporting the synthesis and the pharmacological characterisation of a bromine-76 derivative of dexetimide suitable for PET studies. The radiosynthesis of [7‘Br]-4-bromodexetimide ([7‘Br]-BDEX) was carried out by bromination via electrophilic bromodesilylation with no carrier added [76Br]NT-I4. During the preparation of this radiopharmaceutical a number of reaction conditions and reagents were examined. Oxidising agent such as peracetic acid and dichloramine-T were evaluated and found inefficient while chloramine-T appeared the reagent of choice. Peracetic acid reactions were carried out in acetic acid with radiochemical yields of 6% obtained. Dichloromi.ne~T reactions were conducted in both methanol and TFA solvent with radiochemical yields of 10% and 24% respectively. The choramine-T reactions were most efficient but were also concentration and solvent dependent. The optimum labelling conditions were found to be the use of chloramine-T (10-3M) in 0.1N HC1 at room temperature for l5 min followed by addition of a sodium metabisulte solution (fig. 1). Under these conditions the radiochemical yield reaches 80%. The purification and isolation of the radiotracer from the reaction mixture was carried out by HPLC on a µ-Bondapaku-Bondapak C18 column (300 x 7.8 mm) with a mixture of acetonitrile and ammonium acetate buffer (45:55) as the mobile phase and a ow rate of 2.5 ml/min while UV absorption was measured at 239 nm. Radiochemical and chemical purities assessed by radio-TLC and HPLC were 98% with a specific activity of 11 GBq/µmol/L.
166dysprosium-166holmium in vivo generator
(Kyoto University, 1983-10-10) Mirzadeh, S; Di Bartolo, N; Smith, SV; Lambrecht, RM
Recently, there has been an increasing interest in 166lHo (t1/2=26.8 n, 100% β−, Eβ av=666 Kev) for various therapeutic applications (1-2). A novel approach to deliver this isotope to tissue is via the in-vivo decay of its 81.5-h parent, 166Dy (100% β−, Eβav=l3O MeV) - an in- vivo generator system (3). lt is hoped the flexibility afforded by using this parent-daughter system may result in the reduction of radiation dose to sensitive non-target tissues which until now has limited the efficacy of the radiotherapy. In this scenario, the 166Dy-radiopharmaceutical prepared from pure 166Dy is attached to a tumour specific antibody. During the in vii/0 localisation of the radiolabelled antibody, the resultant dose to non-targeted tissues is reduced because of sub-equilibrium amounts of 166Ho. Once the l66Dy labelled radiopharmaceutical has localised in the target tissue the therapeutic dose can be generated by the decay of its 166Ho daughter. A critical question for the in vivo 166Dy/166Ho generator system is whether translocation of the daughter nucleus occurs following the uptake of the parent at the target site. in an effort to address this question the biodistribution of 166Dg-DTPA was performed, and the bone uptake was carefully analysed for both 166Dy and 166Ho in a gamma-spectrometer employing a Ge(Li) detector. The choice of Dy-DTPA was based on a previous report (4) that the integrity of the 166Ho-DTPA complex is preserved following its formation via 166Dy-DTPA β− decay.
Carrier-free 166Ho from 166Dy/166Ho biomedical generator system
(Kyoto University, 1983-10-25) Mirzadeh, S; Hetherington, E; Knapp, FF; Lambrecht, RM
Holmium-166 (166 Ho) is a potential candidate for various therapeutic applications (1-2) due to its attractive properties which include emission of high-energy β− particles (Eav=666 MeV), an appropriate half-life (t1/2=26.4 h) and decay to stable daughter. ln addition, 166Ho has chemical characteristics suitable for protein labelling through bifunctional chelates. Holmium-166 also emits a low intensity and low energy γ-rays (80 keV, 6%) suitable for imaging. Due to the absence of high energy γ-rays in its decay, 166Ho may be used for outpatient therapy without significant external radiation to other individuals. Although 166Ho, with a moderate specific activity, can be produced by a simple neutron capture reaction, interestingly, its radionuclidic parent (81 .5-h 166Dy) can serve as a source of high specific activity 166Ho. ln certain applications, such as protein labelling, the use of a high specific activity radioisotope is essential. In addition, generator produced 166Ho is free from 1200-γ 166mHo. This isotope is unavoidably coproduced with 166Ho by the 165Ho[n,γ] reaction (3).
Pre-clinical evaluation of 188W/188Re biomedical generator
(Kyoto University, 1983-10) Kamioki, H; Mirzadeh, S; Lamcrecht, RM
In order to assess the performance of clinical scale generators, a 13.5 mCi generator has been prepared and evaluated for 188Re Re yield and elution profile, and 188W breakthrough using various reagents. The generator is alumina-based and eluted on a bi-weekly schedule. The results for a five-week evaluation period are presented. To address the problem of low specific volume (1), the normally used saline solution (as eluent) was replaced by reagents which could be easily destroyed by gentle evaporation from acidic solution (e.g. NH4CI and NH4NO3). Tungsten-188 with a specific activity of ~5 mCi/mg and activity concentration of ~13.5 mCi/ml in 0.1 M NaOH was purchased from ORNL. The generator column (13x21 mm) was fabricated with a coarse glass frit support at the bottom and held 750 mg of alumina (80-120 mesh, pre-equilibrated with 0.01 _M_ HNO3). One ml of the 188W stock solution (~3 mg) was titrated with 1 M HNO3 until pH 2-3 was obtained. The mixture was loaded on the column and 188Re was typically eluted with 4x10 ml portions of various eluents. At the end of each elution, the generator was equilibrated with 10 ml of the next eluent and then was purged dry. This was to reduce the effects of radiolysis which has been shown to result in erratic yield. The 10-ml eluents were collected directly in 10-ml injection vials and the activity of 188Re was measured without further dilution with a calibrated ionisation chamber. After about 2 weeks of decay to insure the equilibrium, the samples were recounted at the surface of a Ge(Li) detector and the breakthrough of 188W was evaluated from the intensity of the 155 keV y-ray of 188Re. The yield and elution profile of 188Re for various reagents are shown in Fig. 1 and 2, respectively. Within 9 elutions, the yield of 188Re decreased from 80% to 70%. As shown in Figure 2, replacement of Na+ ion with H+ or NH4+ ions in the eluent had no observable effect on the 188Re elution behaviour. Consistent with previously reported results obtained from a 1 mCi generator (2), the optimum concentration of cations for sharp elution of Re (in the 1st 10 ml of eluent) is about 0.05 M. Concentrations below this optimal value resulted in an increase in retention time as well as an increase in the FWHM of elution curve (2,3). No effect was observed due to replacement of the CI counter ions with N03 ions (Re in nitrate solutions could be further purified and concentrated in an anion exchange column) (2).

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