International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology最新文献

A new PET radiotracer for in vivo labeling of serotonin (5-HT) uptake sites, cis-N, N-[¹¹C]dimethyl-3-(2′,4′-dichlorophenyl)-indanamine, cis-[¹¹C]DDPI, was synthesized and its biological behavior was studied. The radiosynthesis of cis-[¹¹C]DDPI was performed by N-methylation of cis-N-methyl-3-(2′,4′-dichlorophenyl)-indanamine with [¹¹C]iodomethane. The average radiochemical yield was approx. 8%, with an average specific activity of 600mCi/μmol. Following intravenous administration, cis-[¹¹C]DDPI accumulated in mouse brain regions rich in 5-HT uptake sites, such as olfactory tubercles, hypothalamus and frontal cortex. Following pre-injection of 1 mg/kg of paroxetine, a high affinity 5-HT uptake blocker, the binding of cis-[¹¹C]DDPI in the olfactory tubercles, hypothalamus and frontal cortex was decreased by 23, 25 and 16%; this corresponds to 73, 82 and 59% of the specific binding in these regions. These results suggest that the accumulation of cis-[¹¹C]DDPI in the tissues rich in 5-HT sites is a result of specific binding of cis-[¹¹C]DDPI to 5-HT uptake sites. Due to the relatively high non-specific uptake and slow clearance of this compound from non-specific binding sites, the ratio between specific and non-specific binding increased slowly with time, reaching 1.5:1 at 60 min after injection.

The distribution of selenate and selenite selenium in C57L/J mice during the progression of BW7756 murine hepatoma was investigated using intra-ocular injection with the oxyanions labeled with ⁷⁵Se radioisotope. Comparison is made with the normal distribution of selenium studied by the RIXRF method. The trace elemental profiles, TEP, for the two oxidation states are compared in healthy and disease states. It has been found that the presence of tumor significantly changes the level of tracer in various uninvolved organs. These changes are prominent in the early growth phase of the tumor. The two oxidation states show differences in the TEP for kidney, spleen, stomach and testes.

[¹²³I]2′-ISP was readily prepared using a radioiodine exchange reaction with a radiochemical yield of approx. 50% after HPLC purification. The radiochemical purity of the product was more than 98% and the specific activity was 5.55–11.1 GBq/μmol. Biodistribution studies performed in mice indicated that injection of [¹²³I]2′-ISP with albumin produced a higher gastric uptake and a lower brain uptake than injection of the radioligand in a weakly acidic solution. In addition, toxicity tests performed in mice demonstrated that acute toxic effects would be very unlikely to be encountered if 2′-ISP was used for diagnostic purposes. A preliminary imaging study with [¹²³I]2′-ISP in a healthy human volunteer showed its specific uptake by the basal ganglia, a region of the brain known to have a high density of D₂ dopamine receptors.

A biodistribution study of [¹³N]ammonia in rats showed a high accumulation of radioactivity in the pancreas soon after the intravenous injection of this tracer. In humans, the pancreas was also clearly visualized by dynamic positron emission tomography soon after the intravenous injection of [¹³N]ammonia. To investigate the mechanism of the pancreatic accumulation of [¹³N]ammonia, in vitro studies with pancreatic slices and in vivo biodistribution and metabolism studies were carried out in rats. The results indicated that [¹³N]ammonia enters the pancreas from the blood by diffusion at a rate dependent on local blood flow, and then is rapidly incorporated into the amino acid fraction (mainly the glutamine fraction), followed by its incorporation into protein. These findings suggest that [¹³N]ammonia could be useful for diagnostic imaging of the pancreas.

A new method for labeling preformed liposomes with technetium-99m (^99mTc) has been developed which is simple to perform and stable in vivo. Previous ^99mTc-liposome labels have had variable labeling efficiencies and stability. This method consistently achieves high labeling efficiencies (> 90%) with excellent stability. A commercially available radiopharmaceutical kit—hexamethylpropyleneamine oxime (HM-PAO)—is reconstituted with ^99mTcO^−₄ and then incubated with preformed liposomes that encapsulate glutathione. The incubation takes only 30 min at room temperature. Liposomes that co-encapsulate other proteins such as hemoglobin or albumin, in addition to glutathione, also label with high efficiency. Both in vitro and in vivo studies indicate good stability of this label. Rabbit images show significant spleen and liver uptake at 2 and 20 h after liposome infusion without visualization of thyroid, stomach or bladder activity.

This labeling method can be used to study the biodistribution of a wide variety of liposome preparations that are being tested as novel drug delivery systems. This method of labeling liposomes with ^99mTc may also have applications in diagnostic imaging.

Carazolol is a high affinity beta-adrenergic receptor antagonist which is relatively non-specific for the receptor subtypes. The labeling of the two enantiomers of this compound with carbon-11, including the synthesis of the required labeling precursors, is reported. The yield and specific activity are sufficient for use in positron tomography. Biodistribution and specific receptor binding studies show the labeled material to be of interest for further investigation as a radiopharmaceutical for positron tomography.

Anti-human serum albumin antibody (Ab) was used as a model antibody. Ab was conjugated with DTPA using cyclic DTPA dianhydride reaction and radiolabeled with ¹¹¹In. The labeled Ab was purified by affinity chromatography. Size exclusion HPLC of this product showed 62% of ¹¹¹In bound to monomeric Ab and 38% of the activity bound to antibody oligomers with molecular weights ranging from 300,000 to 450,000. The labeled antibody preparation was injected into the tail vein of rats. The radioactive substances in serum and the supernatant from liver homogenates were analyzed for molecular weight and immunoreactivity. Size exclusion HPLC of the serum samples indicated that the monomeric and dimeric Abs disappeared from the serum at a similar rate over a 48 h period. In addition, a new radioactive substance with an estimated molecular weight of 35,000 appeared in the serum. The immunoreactive fraction of the circulating ¹¹¹In substances decreased slowly, somewhat proportional to the appearance of the metabolite. On the other hand, the immunoreactivity of the ¹¹¹In substances in the supernatant from the liver homogenate decreased rapidly and no appreciable immunoreactivity was observed after 48 h. The labeled antibody was catabolized very rapidly in the liver and the major activity in the supernatant was associated with a small molecular weight metabolite which had a HPLC retention time identical to that of DTPA-¹¹¹In. The second metabolite had an estimated molecular weight of 35,000. No radioactivity was associated with transferrin.

The potent dopamine D-2 ligands (S)-2,3-dimethoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-[¹⁸F]fluoropropyl)benzamide (¹⁸F-1) and (S)-2,3-dimethoxy-N-[(1 -ethyl-2-pyrrolidinyl)methyl]-5-(3-[¹⁸F]fluoropropyl)-6-hydroxybenzamide (¹⁸F-2) were prepared in high specific activity and 5–25% overall radiochemical yields. Benzamide 1 possessed a lower in vitro binding affinity for the D-2 receptor than salicylamide 2, but the in vivo striatal-to-cerebellar radioactivity concentration ratios ($\text{St}\text{Cb}$) in rats and dogs were nearly identical for the two compounds. Compound ¹⁸F-2 was more lipophilic than ¹⁸F-1, and its increased penetration into and retention by striatal tissue was matched by an increase in non-specific binding in the cerebellum. Cerebral cortex radioactivity concentration levels in dogs were similar to cerebellum levels. The binding of ¹⁸F-labelled 1 and 2 displayed regional brain distribution patterns consistent with known dopamine D-2 receptor densities and was selectively blocked in the striatum of rats by dopamine D-2 antagonists. The binding of ¹⁸F-1 was found to be stereoselective, as the ¹⁸F-labelled (R)-enantiomer displayed no selective retention in the striatum of dogs. High levels of radioactivity were found in the bones of rats following the injection of ¹⁸F-1 and ¹⁸F-2, indicating that in vivo defluorination had occurred; however, no bone radioactivity was observed in dogs following the injection of these radioligands. Compound ¹⁸F-1 was displaced from the striatum of dogs by both d-amphetamine-stimulated dopamine release and haloperidol at doses of 1 and 0.5 mg/kg, respectively, while compound ¹⁸F-2 was displaced from the dog striatum only by haloperidol at these doses. The radioligand ¹⁸F-2 holds promise for positron emission tomography studies of the dopamine D-2 receptor system based upon its selective, potent binding and resistance to displacement by endogenous dopamine.

The development of radioligands capable of imaging brain receptors depends on, amongst other factors, the ability of such compounds to penetrate the blood-brain barrier. We describe an ex vivo binding technique for measuring the brain concentration of peripherally administered unlabeled compounds. This technique can be used early in the development of putative radioligands. The pharmacokinetics of brain penetration of three muscarinic antagonists are described: QNB, BrQNB and the 2-thienyl derivative of BrQNB and were found to compare favorably to previous studies using [³H]QNB. These studies demonstrate the effectiveness of ex vivo binding in assessing the brain concentration of peripherally administered unlabeled compounds.