Regional distribution study of brain perfusion and metabolic agents in normal and tumour bearing rat brains using autoradiographic technique

Regional distribution of brain perfusion imaging agents, [¹³¹I]N,N,N′-trimethyl-N′-[2-hydroxy-3-methyl-5-iodobenzyl]1,3 propanediamine (HIPDM) and [¹³¹I]N-isopropyl-p-iodoamphetamine (IMP), was compared with the distribution of patterns of [¹⁴C]l-methionine and [¹⁴C]d-glucose in normal and tumour bearing rat brains using autoradiographic technique. There was higher concentration of the radiopharmaceutical in grey than white matter in normal rat brain. Autoradiographs of brain tumour sections showed very low uptake of [¹³¹I]HIPDM and [¹³¹I]IMP as compared to normal brain tissue. There was moderate concentration of [¹⁴C]d-glucose and avid uptake of [¹⁴C]l-methionine in tumours. Autoradiographic study is useful for evaluating distribution patterns of radiopharmaceuticals.     

Synthesis and biological evaluation of radio-iodinated benzimidazoles as SPECT imaging agents for NR2B subtype of NMDA receptor

In this study, the benzimidazole derivatives were synthesized and evaluated as imaging agents for the NR2B subtype of NMDA receptor. Among these ligands, 2-{[4-(4-iodobenzyl)piperidin-1-yl]methyl}benzimidazol-5-ol (8) and N-{2-[4-(4-iodobenzyl)-piperidin-1-ylmethyl]benzoimidazol-5-yl}-methanesulfonamide (9) exhibited high affinity for the NR2B subunit (K_i values; 7.28 nM for 8 and 5.75 nM for 9). In vitro autoradiography experiments demonstrated high accumulation in the forebrain regions but low in the cerebellum for both [¹²⁵I]8 and [¹²⁵I]9. These regional distributions of the radioligands correlated with the expression of the NR2B subunit. The in vitro binding of these ligands was inhibited by NR2B antagonist but not by other site ligands, which suggested the high selectivity of [¹²⁵I]8 and [¹²⁵I]9 for the NR2B subunit. In mice, the regional brain uptakes of [¹²⁵I]8 and [¹²⁵I]9 at 5–180 min after administration were 0.42–0.56% and 0.44–0.67% dose/g, respectively. The brain-to-blood ratio of [¹²⁵I]8 at 180 min was reduced by 34% in the presence of non-radioactive ligands and by 59% in the presence of the NR2B ligand Ro-25,6981. These results indicated that [¹²⁵I]8 could be partially bound to the NR2B subunit in vivo. Although the brain uptake of these benzimidazole derivatives was too low to allow for in vivo SPECT imaging, these compounds might be useful scaffolds for the development of imaging probes specific for the NMDA receptors.     

Synthesis and bioevaluation of radioiodinated nitroimidazole hypoxia imaging agents by one-pot click reaction

Eight radioiodinated 2-nitroimidazole derivatives for use as hypoxia imaging agents were synthesized by one-pot click reaction using four azides, two alkynes, and [¹³¹I]iodide ions and evaluated by hypoxic cellular uptake and biodistribution experiments. The results suggested that radiotracers with suitable partition coefficients (log P: −0.2–1.2) were more likely to have higher hypoxic cellular uptake. Among these eight molecules, [¹³¹I]15 ([¹³¹I]-(5-iodo-1-(2-(2-(2-nitro-1H-imidazol-1-yl)ethoxy)ethyl)-4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazole)) had a suitable log P (0.05 ± 0.03) and contained two 2-nitroimidazole groups. The hypoxic/aerobic cellular uptake ratio of [¹³¹I]15 was 4.4 ± 0.5, and the tumor/blood (T/B) and tumor/muscle (T/M) ratios were 2.03 ± 0.45 and 6.82 ± 1.70, respectively. These results suggested that [¹³¹I]15 was a potential hypoxia imaging agent.     

Labeling proteins using aryl iodide acylation agents: Influence of meta vs para substitution on in vivo stability

The effect of para vs meta substitution on the biological behavior of an intact antibody and an F(ab′)₂ fragment was investigated. Paired-label studies were performed using 81C6 IgG and OC 125 F(ab′)₂ labeled using the N-succinimidyl esters of both p-[¹²⁵I]- and m-[¹³¹I]iodobenzoate as well as with the potential catabolites, p-[¹²⁵I]- and m-[¹³¹I]iodobenzoic acid. In all 3 studies, up to 55% lower uptake of ¹³¹I in thyroid and stomach was observed, suggesting that the m-substituted species were more inert to dehalogenation in vivo.     

Design,synthesis, and biological evaluation of radioiodinated benzo[d]imidazole-quinoline derivatives for platelet-derived growth factor receptor β (PDGFRβ) imaging

Several malignant tumors and fibrotic diseases are associated with PDGFRβ overexpression and excessive signaling, making this receptor attractive for molecular targeting and imaging approaches. A series of benzo[d]imidazole-quinoline derivatives were designed and synthesized to develop radioiodinated compounds as PDGFRβ-specific imaging probes. The structure activity relationship (SAR) evaluation of the designed compounds was performed. Among them, 2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (5a) and 4-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (5d) exhibited a relatively high PDGFRβ-TK inhibitory potency, whereas iodinated 5a derivative 5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (8) exhibited a superior inhibitory potency as PDGFRβ inhibitor than iodinated 5d derivative 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (11). Furthermore, [¹²⁵I]8 and [¹²⁵I]11 were synthesized and evaluated for PDGFRβ radioligand ability, both in vitro and in vivo. Cellular uptake experiments showed that [¹²⁵I]8 had a higher uptake in BxPC3-luc cells as PDGFRβ-positive cells than [¹²⁵I]11. Incubation of [¹²⁵I]8 after pretreatment of PDGFRβ ligands significantly reduced the uptake of [¹²⁵I]8. In biodistribution experiments using tumor-bearing mice, [¹²⁵I]8 accumulation in the tumor 1?h postinjection was higher than that of the benzo[d]imidazol-quinoline derivative [¹²⁵I]IIQP, used in our previous research. These results indicate that [¹²⁵I]8 could be a promising PDGFRβ imaging agent. Although its clinical application requires further structural modifications, the results obtained in this research may be useful for the development of PDGFRβ-specific radioligands.     

Synthesis and evaluation of novel radioiodinated PSMA targeting ligands for potential radiotherapy of prostate cancer

Radioligand therapy (RLT) using prostate-specific membrane antigen (PSMA) targeting ligands is an attractive option for the treatment of Prostate cancer (PCa) and its metastases. We report herein a series of radioiodinated glutamate-urea-lysine-phenylalanine derivatives as new PSMA ligands in which l-tyrosine and l-glutamic acid moieties were added to increase hydrophilicity concomitant with improvement of in vivo targeting properties. Compounds 8, 15, 19a/19b and 23a/23b were synthesized and radiolabeled with ¹²⁵I by iododestannylation. All iodinated compounds displayed high binding affinities toward PSMA (IC₅₀ = 1–13 nM). In vitro cell uptake studies demonstrated that compounds containing an l-tyrosine linker moiety (8, 15 and 19a/19b) showed higher internalization than MIP-1095 and 23a/23b, both without the l-tyrosine linker moiety. Biodistribution studies in mice bearing PC3-PIP and PC3 xenografts showed that [¹²⁵I]8 and [¹²⁵I]15 with higher lipophilicity exhibited higher nonspecific accumulations in the liver and intestinal tract, whereas [¹²⁵I]19a/19b and [¹²⁵I]23a/23b containing additional glutamic acid moieties showed higher accumulations in the kidney and implanted PC3-PIP (PSMA+) tumors. [¹²⁵I]23b displayed a promising biodistribution profile with favorable tumor retention, fast clearance from the kidney, and 2–3-fold lower uptake in the liver and blood than that observed for [¹²⁵I]MIP-1095. [^125/131I]23b may serve as an optimal PSMA ligand for radiotherapy treatment of prostate cancer over-expressing PSMA.     

Procurement of radioiodinated glucose derivative and its biological character

Radiolabeled glucose derivatives are attracting great interest in the clinical field. Development of an analogous substrate labeled with a practical radionuclide, ¹²³I, is most desirable, however, no radioiodine labeled glucose derivative has been reported as being chemically and biologically compatible. Thus, in the present study, a glucose derivative substituted at the C-2 position by a p-iodobenzyl group, a 2-O-(p-iodobenzyl)-d-glucose (IBG) was designed and its synthesis was carried out.A very easy and simple synthetic method was developed, and the obtained IBG showed appropriate purity and stability for its radioiodination. [¹²⁵I]IBG was obtained by radioisotopic exchange reaction with high radiochemical purity and radiochemical yield, requiring no purification. The good in vivo and in vitro stability and the chemical and biological characteristic displayed by the new [¹²⁵I]IBG stimulated the measurement of the brain uptake index (BUI). In the presence of glucose, brain uptake inhibition was detected, a good indication of a glucose carrier mediator for the transport of [¹²⁵I]IBG through the blood-brain barrier, a similar feature to that of [¹⁴C]glucose or 3-O-[¹⁴C]methylglucose. The newly designed ligand IBG holds good promise for the study of regional cerebral glucose utilization, should the ¹²³I become available.     

Intrathyroidal iodine metabolism in the rat. The influence of diet and the administration of thyroid-stimulating hormone

1. Ratios of mono[¹³¹I]iodotyrosine and di[¹³¹I]iodotyrosine (R values) and the incorporation of ¹³¹I into iodothyronines have been estimated in rat thyroid glands from 30min. to 38hr. after the administration of [¹³¹I]iodide. 2. In rats receiving a powdered low-iodine diet the R values were close to unity and did not change with time after the administration of [¹³¹I]iodide. In rats receiving a commercial pellet diet the R values fell from a mean of 0·8 at 30min. after [¹³¹I]iodide administration to 0·49 at 38hr. 3. Administration of 0·5–2·0i.u. of thyroid-stimulating hormone before giving the injection of [¹³¹I]iodide caused a small diminution in the R value when the time between injecting [¹³¹I]iodide and killing the animal was 16hr. or more. 4. Iodothyronines represented a greater percentage of the total thyroid-gland radioactivity in the iodine-deficient animals than in animals fed on the pellet diet. Thyroid-stimulating hormone had little effect, if any, on the iodothyronine contents.     

Synthesis and in vitro evaluation of radioiodinated indolequinones targeting NAD(P)H: Quinone oxidoreductase 1 for internal radiation therapy

NAD(P)H: quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase and is highly expressed in many human solid cancers. Because NQO1 can be induced immediately after exposure to ionizing radiation, we aimed to develop an NQO1-targeted radiolabeled agent to establish a novel internal radiation therapy that amplifies the therapeutic effects when combined with external radiation therapy. We designed three NQO1-targeted radioiodinated compounds including two ether linkage compounds ([¹²⁵I]1 and [¹²⁵I]2) and a sulfide linkage compound ([¹²⁵I]3) based on the selective binding of indolequinone analogs to the active site of NQO1 by the stacking effect. These compounds were successfully prepared using an oxidative iododestannylation reaction with high radiochemical yields and purity. In NQO1-expressing tumor cells, [¹²⁵I]1 and [¹²⁵I]2 were readily metabolized to p-[¹²⁵I]iodophenol or m-[¹²⁵I]iodophenol and [¹²⁵I]I⁻, whereas over 85% of the initial radioactivity of [¹²⁵I]3 was observed as an intact form at 1 h after incubation. The cellular uptake of [¹²⁵I]3 was significantly higher than those of [¹²⁵I]1 and [¹²⁵I]2. The uptake of [¹²⁵I]3 was specific and was dependent on the expression of NQO1. These data suggest that the novel NQO1-targeted radioiodinated compound [¹²⁵I]3 could be used as a novel internal radiation agent for the treatment of cancer.     

Radiolabeling and initial biological evaluation of [18F]KBM-1 for imaging RAR-α receptors in neuroblastoma

Retinoic acid receptor alpha (RAR-α) plays a significant role in a number of diseases, including neuroblastoma. Children diagnosed with high-risk neuroblastoma are treated 13-cis-retinoic acid, which reduces risk of cancer recurrence. Neuroblastoma cell death is mediated via RAR-α, and expression of RAR-α is upregulated after treatment. A molecular imaging probe that binds RAR-α will help clinicians to diagnose and stratify risk for patients with neuroblastoma, who could benefit from retinoid-based therapy. In this study, we report the radiolabeling, and initial in vivo evaluation of [¹⁸F]KBM-1, a novel RAR-α agonist. The radiochemical synthesis of [¹⁸F]KBM-1 was carried out through KHF₂ assisted substitution of [¹⁸F]^? from aryl-substituted pinacolatoesters-based retinoid precursor. In vitro cell uptake assay in human neuroblastoma cell line showed that the uptake of [¹⁸F]KBM-1 was significantly inhibited by all three blocking agents (KBM-1, ATRA, BD4) at all the selected incubation times. Standard biodistribution in mice bearing neuroblastoma tumors demonstrated increased tumor uptake from 5 min to 60 min post radiotracer injection and the uptake ratios for target to non-target (tumor: muscle) increased 2.2-fold to 3.7-fold from 30 min to 60 min post injection. Tumor uptake in subset of 30 min blocking group was 1.7-fold lower than unblocked. These results demonstrate the potential utility of [¹⁸F]KBM-1 as a RAR-α imaging agent.     

Synthesis and biological evaluation of radioiodinated 2NUBTA as a cerebral ischemia marker

N-[4-(Benzothiazol-2-yl)phenyl]-11-(2-nitroimidazole-1-yl)undecanamide (2NUBTA) was synthesized and radiolabeled with iodine-131. In vitro evaluation of the [¹³¹I]2NUBTA using murine sarcoma S180 cells showed increase in radioactivity in hypoxic cells up to 4 h, while it was not in aerobic cells. Its potential as a cerebral ischemia marker was evaluated using gerbil stroke models that had been subjected to right common carotid artery ligation to produce cerebral ischemia. The uptake in the right cerebral hemisphere decreased slowly than that of the left and the right/left hemisphere uptake ratios increased with time going on. It indicated that [¹³¹I]2NUBTA might be a possible cerebral ischemia marker.     

Evidence for a secretion of thyroxine by isolated hog thyroid cells

Isolated thyroid cells prepared from hog thyroid glands by tryptic dispersion were incubated with ¹³¹I⁻ for 1–6 h. Free [¹³¹I]thyroxine was identified in the incubation medium by three chromatographic methods. Neither [¹³¹I]iodotyurosines nor [¹³¹I]triiodothyronine were detected. The [¹³¹I]thyroxine released in the medium by 100 μl of cells (packed cell volume) after a 6-h incubation period amounted to 1.16% (S.E. = ± 0.39) of the total radioactivity. The medium [¹³¹I]thyroxine represented 15–25% of the total [¹³¹I]thyroxine synthesized during the 6 h of incubation. Thyrotropin, 1–60 munits/ml, increased the medium [¹³¹I]thyroxine content 2–4 fold. Dibutyryl cyclic AMP mimicked the effect of thyrotropin. The amount of medium [¹³¹I]thyroxine was strictly related to the amount of incubated cells but was independent of the volume of the incubation medium. When prelabeled cells were incubated in the presence of methimazole the increase in medium [¹³¹I]thyroxine was quantitatively related to a decrease in the intracellular [¹³¹I]thyroxine. Addition of dinitrotyrosine, an inhibitor of the deiodinase activity, induced the release of iodotyrosines in the incubation medium. That the incubation supernatant of isolated thyroid cells did contain free thyroxine but no iodotyrosines suggests that the normal mechanisms of proteolysis of thyroglobulin and deiodination of iodotyrosines inside the cells are preserved. From these data, it was concluded that the thyroxine release by isolated cells represents a real secretion.     

Radioprotection après injection thérapeutique de [131I]-mIBG : données préalables à l’ouverture du protocole MIITOP-0607

IntroductionThe MIITOP-0607 protocol, studying the efficiency of administration of topotecan and myelosupressive [¹³¹I]-mIBG therapy in children affected by neuroblastoma, needed to assess irradiation risks on staff and family of children to obtain the agreement of the Autorité de sûreté nucléaire (ASN). Our aim was to quantify irradiation of the staff during preparation of the mIBG and to assay the irradiation and contamination of the accompanying persons.Patient and methodsRadiation exposure of the staff was measured during the preparation, transport and administration of the first treatment. Salivary and urinary excretions were monitored well as the atmospheric radioactivity. Radiation exposure and contamination of the accompanying persons were also measured.ResultsFinger dose of 3 mSv and whole body dose of 50 μSv were estimated for preparation of an 11.1 GBq syringe. Irradiation from urinary activity can be as low as 100 μSv if a dedicated device is used. Salivary excretion decreased rapidly during the first 24 hours. Atmospheric contamination always remained below 25 Bq m^?3. Total irradiation of the accompanying persons is about 2.35 mSv for the two consecutive injections (9,3 and 11,1 GBq). Internal contamination occurred only once and corresponded to a 27 μSv whole body irradiation and 670 μSv thyroid irradiation.ConclusionThis study shows the safety of [¹³¹I]-mIBG treatments using high activities. The involved dose is not negligible but seems to be acceptable in the specific paediatric oncology context if radioprotection instructions are met and if optimization of protocols is performed.     

Synthesis and evaluation of novel benzothiazole derivatives based on the bithiophene structure as potential radiotracers for β-amyloid plaques in Alzheimer’s disease

In this study, six novel benzothiazole derivatives based on the bithiophene structure were developed as potential β-amyloid probes. In vitro binding studies using Aβ aggregates showed that all of them demonstrated high binding affinities with K_i values ranged from 0.11 to 4.64 nM. In vitro fluorescent staining results showed that these compounds can intensely stained Aβ plaques within brain sections of APP/PS1 transgenic mice, animal model for AD. Two radioiodinated compounds [¹²⁵I]-2-(5′-iodo-2,2′-bithiophen-5-yl)-6-methoxybenzo[d]thiazole [¹²⁵I]10 and [¹²⁵I]-2-(2,2′-bithiophen-5-yl)-6-iodobenzo[d]thiazole [¹²⁵I]13 were successfully prepared through an iododestannylation reaction. Furthermore, in vitro autoradiography of the AD model mice brain sections showed that both [¹²⁵I]10 and [¹²⁵I]13 labeled the Aβ plaques specifically with low background. In vivo biodistribution studies in normal mice indicated that [¹²⁵I]13 exhibited high brain uptake (3.42% ID/g at 2 min) and rapid clearance from the brain (0.53% ID/g at 60 min), while [¹²⁵I]10 showed lower brain uptake (0.87% ID/g at 2 min). In conclusion, these preliminary results of this study suggest that the novel radioiodinated benzothiazole derivative [¹²⁵I]13 may be a candidate as an in vivo imaging agent for detecting β-amyloid plaques in the brain of AD patients.     

Highly efficient method for 125I-radiolabeling of biomolecules using inverse-electron-demand Diels–Alder reaction

In this report, we present a rapid and highly efficient method for radioactive iodine labeling of trans-cyclooctene group conjugated biomolecules using inverse-electron-demand Diels–Alder reaction. Radioiodination reaction of the tetrazine structure was carried out using the stannylated precursor 2 to give ¹²⁵I-labeled product ([¹²⁵I]1) with high radiochemical yield (65 ± 8%) and radiochemical purity (>99%). For radiolabeling application of [¹²⁵I]1, trans-cyclooctene derived cRGD peptide and human serum albumin were prepared. These substrates were reacted with [¹²⁵I]1 under mild condition to provide the radiolabeled products [¹²⁵I]6 and [¹²⁵I]8, respectively, with excellent radiochemical yields. The biodistribution study of [¹²⁵I]8 in normal ICR mice showed significantly lower thyroid uptake values than that of ¹²⁵I-labeled human serum albumin prepared by a traditional radiolabeling method. Therefore [¹²⁵I]8 will be a useful radiolabeled tracer in various molecular imaging and biological studies. Those results clearly demonstrate that [¹²⁵I]1 will be used as a valuable prosthetic group for radiolabeling of biomolecules.     

Two new ion-pair complexes containing derivatives of substituted benzyl isoquinolinium and bis(maleonitriledithiolato)nickelate monoanion: 3D crystal structures, magnetic properties and theoretical analyses

Syntheses, structural characterizations, magnetic behaviors and theoretical analyses of two new ion-pair complexes, [IFBzIQl][Ni(mnt)₂](1) and [IClBzIQl]₂[Ni(mnt)₂]₂ · MeCN(2) [IFBzIQl][Ni(mnt)₂] ([IFBzIQl]⁺ = 1-(2′-fluoro-4′-iodobenzyl)isoquinolinium, [IClBzIQl]⁺ = 1-(2′-chloro-4′-iodobenzyl)isoquinolinium, mnt²⁻ = maleonitriledithiolate), have been investigated. In crystal of 1, the [Ni(mnt)₂]⁻ anions and the [IFBzIQl]⁺ cations stack into an alternating column through π?π stacking interactions. The anions of both 1 and 2 form a dimer via π?π stacking and S?S short interactions between the [Ni(mnt)₂]⁻ anions. The overlapping mode of two neighboring [Ni(mnt)₂]⁻ anions in the dimer is the Ni-ring fashion with a Ni?Ni distance of 4.076 Å for 1, and ring-ring fashion with the Ni?Ni and S?S distances being 4.395 and 3.593 Å for 2. Some weak interactions such as π?π, C?N, C-H?F or C-H?N in 1 and 2 play a crucial role in stacking and stabilizing the crystal lattice, and give a 3D network structure and exchange pathways of the magnetic interaction for 1 and 2. Magnetic susceptibility measurements for 1 and 2 in the temperature range 1.8-300 K show that the overall magnetic behavior indicates the presence of antiferromagnetic interaction, while 2 exhibits an activated magnetic behavior in the high-temperature region (HT) together with a Curie tail in the low-temperature region (LT).     

Radiosynthesis,in vitro and in vivo evaluation of 123I-labeled anandamide analogues for mapping brain FAAH

Fatty acid amide hydrolase (FAAH) is one of the main enzymes responsible for terminating the signaling of endocannabinoids, including anandamide. This paper is the first report of the synthesis, [¹²³I]-labeling and in vitro and in vivo evaluation of anandamide analogues as potential metabolic trapping radioligands for in vivo evaluation of brain FAAH. N-(2-Iodoethyl)linoleoylamide (2) and N-(2-iodoethyl)arachidonylamide (4) were synthesized with good yields (75% and 86%, respectively) in a two steps procedure starting from their respective acids. In vitro analyses, performed using recombinant rat FAAH and [³H]-anandamide, demonstrated interaction of 2 and 4 with FAAH (IC₅₀ values of 5.78 μM and 3.14 μM, respectively). [¹²³I]-2 and [¹²³I]-4 were synthesized with radiochemical yields of 21% and 12%, respectively, and radiochemical purities were >90%. Biodistribution studies in mice demonstrated brain uptake for both tracers (maximum values of 1.23%ID/g at 3 min pi for [¹²³I]-2 and 0.58%ID/g at 10 min pi for [¹²³I]-4). However, stability studies demonstrated the sensitivity of both tracers to dehalogenation.     

A Comparative PET-study of five carbon-11 or fluorine-18 labelled salicylamides. Preparation and in vitro dopamine D-2 receptor binding

Five ¹¹C- or ¹⁸F-labelled salicylamides ([¹¹C]raclopride (I), [¹¹C]eticlopride (II), [¹⁸F]NCQ 258 (III), [¹⁸F]NCQ 134 (IV) and [¹⁸F]NCQ 135 (V)) were prepared. The total radiochemical yields of I–V from EOB were 3–30% (decay-corrected) with an overall synthesis time of 40–110 min. All compounds were isolated by semi-preparative HPLC and the radiochemical purity was > 99%. I–V were in separate experiments injected into Cynomolgus monkeys for PET-examination of ligand distribution in brain in vivo. I–V passed rapidly across the blood-brain barrier. With both analogs I and II there was a high uptake in the striatum, a region with a high density of dopamine D-2 receptors. With the ¹⁸F-labelled analogs III and IV, the uptake in the striatum was almost identical to that in the dopamine receptor poor cerebellum whereas the striatal uptake of V was clearly higher than in the cerebellum. Unlabelled I–V (raclopride, eticlopride, NCQ 258 (VII), NCQ 134 (VIII) and NCQ 135 (IX)) were also prepared and examined in vitro using [³H]raclopride and [³H]spiperone binding to rat striatal dopamine D-2 receptors. A significantly lower affinity was shown for NCQ 258 and NCQ 134 (5 times) compared to that of raclopride and eticlopride, respectively, whereas the affinity of NCQ 135 was similar to that of eticlopride.     

Synthesis and in vitro autoradiographic evaluation of a novel high-affinity radioiodinated ligand for imaging brain cannabinoid subtype-1 receptors

There is strong interest to study the involvement of brain cannabinoid subtype-1 (CB₁) receptors in neuropsychiatric disorders with single photon emission computed tomography (SPECT) and a suitable radioligand. Here we report the synthesis of a novel high-affinity radioiodinated CB₁ receptor ligand ([¹²⁵I]8, [¹²⁵I]1-(2-iodophenyl)-4-cyano-5-(4-methoxyphenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxylate, [¹²⁵I]SD7015). By autoradiography in vitro, [¹²⁵I]8 showed selective binding to CB₁ receptors on human brain postmortem cryosections and now merits labeling with iodine-123 for further evaluation as a SPECT radioligand in non-human primate.     

Radioactive Iodine Therapy Without Recent Antithyroid Drug Pretreatment For Hyperthyroidism Complicated By Severe Hyperbilirubinemia Due To Hepatic Dysfunction: Experience Of A Chinese Medical Center

Objective: The objective of this work is to report our experience with ¹³¹I therapy without recent antithyroid drug (ATD) pretreatment for refractory severe hyperthyroidism complicated by hyperbilirubinemia due to hepatic dysfunction.Methods: Five patients with refractory severe hyperthyroidism were treated with ¹³¹I at 90 to 120 μCi/g-thyroid (total activity, 6.2 to 10.1 mCi). The patients previously had received ATD treatment from 2 months to 12 years and discontinued ATDs from 2 months to 4 years before ¹³¹I treatment due to treatment failure or severe jaundice. Prior to ¹³¹I therapy, the patients were asked to take a low-iodine diet and were treated with bisoprolol fumarate, digoxin, furosemide, S-adenosylmethionine, polyene phosphatidylcholine, and plasma exchange as supportive treatment for related clinical conditions. Four of the patients also received lithium carbonate in conjunction with their ¹³¹I treatment. The patients were followed for 4 to 9 years after ¹³¹I therapy.Results: After ¹³¹I treatment, jaundice disappeared completely within 3 to 4 months in all patients, and liver function tests returned to normal. Concurrent atrial fibrillation and heart failure, leukopenia and thrombocytopenia, or thrombocytopenia and left cardiac enlargement improved remarkably in 3 patients during the follow-up period. Three to 45 months after ¹³¹I treatment, hypothyroidism was noted in the patients and they were treated with L-thyroxine replacement therapy.Conclusion:¹³¹I therapy without recent ATD pretreatment for refractory severe hyperthyroidism complicated by serious jaundice appears to be safe and effective, with good long-term results. It may be the preferred therapy for such patients and should be used as early as possible.Abbreviations:ATD = antithyroid drugFT₄ = free thyroxinePTU = propylthiouracilRAIU = radioactive iodine uptakeTSH = thyroid-stimulating hormone