The chemistry and physical properties of a series of rhenium diamino dithiol (dadt) complexes are described. Liposolubility was enhanced by N-substitution of alkyl chains of C1–C14 length on one ligand structure, with longer chain lengths showing the higher solubility, but with a reduction of radiolabelling yield with 99mTc and 186Re. Among the ReV=O [dadt] complexes synthesized, we found that 2,2,9,9-tetramethyl-4-N-alkyl-4,7-diaza-1,10-decanedithiol (alkyl = C1–C10) resulted in stable and lipiodol-soluble complexes. Biological characteristics of the C6 ligand labelled with 99mTc and 186Re were compared, and indicated that the complexes behaved in a similar manner in rodents. The dadt ligands in combination with 188Re or 186Re and fatty acid oils merit further consideration as endotherapeutic radiopharmaceuticals for treatment of hepatoma and metastatic liver cancer.

Since clinical gene therapy trials have expanded dramatically in the past noninvasive clinical monitoring procedures have to be developed in order to provide information about expression levels, expression kinetics and spatial distribution of transduced therapeutic genes. Such procedures could help to avoid invasive sampling of tissue probes from patients in the near future. In our study, we have employed a mutated version of the low affinity nerve growth factor receptor (Delta LNGFR) lacking the entire cytoplasmic domain and demonstrated specific binding of I-125 radiolabeled nerve growth factor (NGF) for stable Delta LNGFR transduced cells, but not for Delta LNGFR negative parental control cells. Further binding analysis performed in a MicroImager directly confirmed specific binding of NGF radiolabeled with the positron emitting isotope I-124 for LNGFR positive PC12 cells. These results provide a new basis for a future non-invasive Positron Emission Tomography (PET) monitoring in clinical gene therapy trials.

The non-steroidal anti-inflammatory agent 2-amino-methyl-4-tert-butyl-6-iodophenol hydrochloride (MK-447) and some of its analogues were labelled with I-123 and tested in an inflamed rat-paw model. Even though MK-447 has a significant anti-inflammatory activity, and a 2.3 ratio for inflamed site over muscle, its usefullness for scintigraphic detection of inflammation is hindered by its high uptake in the skin. The kinetic resolution of diastereomeric products with chiral dienyl iron complexes was unsuccessful as the signals from the respective H-1 and C-13 NMR spectra were coincident.

The present status and future directions of research and development on radionuclide generator technology are reported. The recent interest to develop double-neutron capture reactions for production of in vivo generators; neutron rich nuclides for radioimmunotherapeutic pharmaceuticals; and advances with ultrashort lived generators is highlighted. Emphasis is focused on: production of the parent radionuclide; the selection and the evaluation of support materials and eluents with respect to the resultant radiochemical yield of the daughter, and the breakthrough of the radionuclide parent; and, the uses of radionuclide generators in radiopharmaceutical chemistry, biomedical and industrial applications. The Zn-62 --> Cu-62, Ni-66 --> Cu-66, Rh-103m --> Rh-103, W-188 --> Re-188 and the Ac-225 --> Fr-221 --> Bi-213 generators are predicted to be emphasized for future development. Coverage of the Mo-99 --> Tc-99m generator was excluded, as it the subject of another review. The literature search ended June, 1996.

Since the publication ofRadiochemistry of Germanium (NAS-NS-3043) in 1961, there have been significant developments on the subject. During the period from 1970 to 1980, the diagnostic utilization of the68Ge→68Ga generator system in nuclear medicine stimulated research in the field. In addition, over the past 30 years there have been many advances in the analytical chemistry of germanium (Ge), owing to the rapid increase in application of Ge in the electronics industry and, most recently, as an important component in infrared spectrometers.

[123I]N-methyl-4-iododexetimide, [123I]MIDEX, and its pharmacologically inactive enantiomer [123I]N-methyl-4-iodolevetimide, [123I]MILEV were prepared via electrophilic iododesilylation using Chloramine-T as oxidising agent followed by N-methylation using methyl iodide. The radiotracers were purified with semi-preparative HPLC with radiochemical yields of 80 +/- 11% (n = 6). The average time of synthesis was 100 min with specific activity > 2000 Ci/mmol. In vitro, the binding of [123I]MIDEX, after addition of carrier, measured on homogenates of rat atrium was Bmax = 4.5 +/- 0.4 pmol/mg protein, Kd = 3.3 +/- 0.2 nM while in the ventricle Bmax = 2.3 +/- 0.2 pmol/mg protein, Kd = 4.0 +/- 1.4 nM. In vitro, the binding of [123I]MILEV was non-specific. The in vivo biodistribution of [123I]MIDEX showed high uptake in the atrium (3.2% ID/g) and left and right ventricles (2.2, 2.5% ID/g respectively) at 5 min followed by clearance. High heart-to-lung and moderate liver-to-lung ratios were obtained during 60 min. Radioactivity in the atrium and ventricles was reduced by pre-administration of the m-AChR antagonist MQNB (1 mg/kg). Pretreatment of rats with other m-AChR ligands, pirenzapine (M1), methoctramine (M2) and 4-DAMP (M3) also resulted in reduction of [123I]MIDEX uptake with methoctramine being the most potent. [123I]MIDEX distribution in the rat heart was not significantly inhibited by pre-administration of selective adrenergic drugs. The uptake was highly stereoselective since the inactive enantiomer, [123I]MILEV, demonstrated very low myocardial retention. The stability of [123I]MIDEX was evaluated by performing a metabolite study on atrium samples which revealed unchanged radiotracer 60 min postinjection. These results suggest that [123I]MIDEX may be a useful single photon agent for in vivo imaging of myocardial m-AChR in humans with [123I]MILEV offering the potential of assessing non-specific binding of the active tracer.

4-[76Br]bromodexetimide and its inactive enantiomer 4-[76Br]bromolevetimide were prepared via electrophilic bromodesilylation using chloramine-T and no-carrier-added (NCA) [76Br]NH4. In vitro, Bmax measured on rat cortex membranes were 3.7 ± 0.2 and <0.07 pmol/mg protein for 4-[76Br]bromodexetimide and 4-[76Br]bromolevetimide, respectively. The kD of 4-[76Br]bromodexetimide was 1.9 ± 0.3 nM. In vivo studies in rats showed specific uptake of 4-[76Br]bromodexetimide in cortex, striatum, thalamus and hippocampus. No specific uptake was observed with 4-[76Br]bromolevetimide. With [76Br]bromodexetimide, positron emission tomography (PET) studies in primates demonstrated a preferential accumulation of the radioactivity in the cortex and striatum which was displaced to the level of cerebellum by dexetimide. With 4-[76Br]bromolevetimide, the radioactivity concentrations in the cortex and striatum were similar to that of cerebellum.

UNLABELLED:Iodine-123-iododexetimide (IDEX) has recently been used for SPECT imaging of muscarinic cholinergic neuroreceptors (mAChR) in humans. We report the human radiation dosimetry, whole-body and normal cerebral distribution of IDEX.METHODS:Serial whole-body planar and brain SPECT scans were performed over 24 hr in four normal subjects. Organ activity was calculated from attenuation-corrected geometric mean counts from ROIs drawn over visible organs. Thigh activity was used for background subtraction. Organ absorbed doses and effective dose were calculated using the MIRD schema. Brain SPECT was performed 6 hr postinjection in ten normal subjects. ROIs placed over cortical and subcortical structures were used to determine brain distribution.RESULTS:The effective dose was 24.7 microSv/MBq. An average of 54% of IDEX remained in the body background. Decay-corrected brain uptake was 6.9% of injected dose at 1 hr, 8.6% at 6 hr and 8.1% at 24 hr. Regional brain distribution showed high uptake in striatum and cortex with low activity in thalamus and cerebellum. At 6 hr, activity relative to striatum was 70% for frontal and parietal cortex, 102% for occipital cortex, 54% for thalamus and 11% for cerebellum.CONCLUSION:Iodine-123-IDEX produced high quality SPECT images with activity at 6 hr reflecting the known distribution of mAChR receptors. The favorable dosimetry of IDEX and high synthetic yield (50%-70%) suggest it to be a suitable agent for clinical studies.

The muscarinic cholinergic receptor antagonist dexetimide and its pharmacologically inactive enantiomer levetimide were labelled with the positron emitter bromine-76. [Br-76]4-Bromodexetimide, [Br-76]BrDEX, and [Br-76]4-bromolevetimide, [Br-76]BrLEV, were prepared via electrophilic bromodesilylation of 4-(trimethylsilyl)dexetimide and 4-(trimethyylsilyl)levetimide with [Br-76]NH4. The use of chloramine-T in acid media resulted in radiochemical yields of 80%. The radiotracers were purified by semi-preparative reverse-phase HPLC. Radiochemical and chemical purities were assessed by radio-TLC and HPLC and found to be 98%. The average time of synthesis including formulation was 60 minutes resulting in average specific activities of 300 mCi/mu mol.

[11C]A-69024, (±)-1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-[11C]methyl-1,2,3,4-tetra-hydroisoquinoline, is a specific and selective dopamine D1 radiotracer. The in vivo biodistribution of this novel radioligand in mice showed a high uptake in the striatum (6.7%ID/g) at 5 min, followed by clearance with a half-life of 16.1 min. As a measure of specificity, the striatal/cerebellar ratio reached a maximum of 7.4 at 30 min post-injection. Radioactivity in the striatum was reduced to the level of the cerebellum by pre-adminstration of the D1 antagonist SCH 23390 (1 mg/kg). Pretreatment of mice with spiperone (D2), 7-hydroxydipropylaminotetralin (7-OH-DPAT) (D3), clozapine (D4), ketanserin (5-HT2/5-HT2C), mazindol (monoamine reuptake), prazosin (α1), and haloperidol (D2/σ) had no inhibitory effect on [11C]A-69024 uptake in the striatum. The dextrorotatory enantiomer of the dopamine antagonist butaclamol inhibited striatal uptake, while the less active isomer (−)-butaclamol did not. [11C]A-69024 binding was inhibited by unlabeled A-69024 in a dose dependent manner (ED50 = 0.3 mg/kg) in the striatum while no change occurred in the cerebellum. [11C]A-69024 warrants further investigation as a PET ligand for examination of central dopamine D1 receptors in humans.

An alumina-based W-188-->Re-188 generator was evaluated for Re-188 yield and elution profile and W-188 breakthrough using various reagents for a three-month period. To address the problem of low specific volume, the generator was eluted with reagents which could be easily destroyed by gentle evaporation from acidic solutions (e.g. NH4Cl and NH4NO3). We also evaluated a proposed ''alumina/anion-exchange'' tandem generator for the preparation of highly purified Re-188 as perrhenic acid. In parallel studies, the adsorption dynamics of tungsten on alumina showed a sharp rise in the tungsten breakthrough at W/Al2O3 ratio of similar to 120 mg/g corresponding to a distribution constant of similar to 8400 from nitrate solution at 0.05 M ionic strength. In adsorption on anion exchange resins, carrier-free Re-188 exhibited a behavior very similar to that of macroscopic quantities of Re. These studies further demonstrated the long and useful shelf-life of W-188-->Re-188 generator.

Recent progress in the development of reactor and cyclotron produced radionuclides, conversion to precursors, synthesis, quality control and biomedical applications are highlighted with examples of prospective radiopharmaceuticals applicable to major diseases of the Australasia region. The merits of cyclotrons and nuclear reactors for medical radioisotopes in the region are cited.

Patients designated to receive 131I-meta-iodobenzylguanadine (mIBG) for the treatment of neural crest tumours have been scanned with 124I-mIBG using the MUP-PET positron camera. Uptake was detected in tumour sites in lung, liver and abdomen. The tomographic images produced have allowed estimates to be made of the concentration of mIBG in both tumour and normal tissue. From these data it is possible to predict the radiation doses that would be achieved using therapy levels (up to 11 GBq) of 131I-mIBG. The levels of tumour uptake are between 0.5 and 2.0 kBq/g indicating that the radiation doses to tumour would be in the range 3 Gy to 7.5 Gy.

Excitation functions were measured for the formation of 122mCs, 121Xe and I-121 from threshold up to 44 MeV in proton induced nuclear reactions on 99.9% enriched 124Xe. The feasibility of 122Xe --> I-122 generator production was investigated. The optimum energy range for the production of 122Xe is E(p) = 43 --> 35 MeV and the thick target yield amounts to 13.5 mCi/mu-Ah. After an appropriate cooling time a generator containing several hundred mCi of 122Xe could be produced. The daughter I-122 could be milked off periodically and would be > 99% pure.