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

Radioiodinated 2-hydroxy-3-(4-iodophenyl)-1-(4-phenylpiperidinyl)propane, 5 (4-HIPP), was synthesized and evaluated as a simple vesamicol-like radiotracer for mapping cholinergic pathways in the brain. Both enantiomers of 5 exhibit significant accumulation (approx. 2% of injected dose) and prolonged retention ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{> 3 h}$) within the rat brain. The accumulation of radioiodinated 5 in the rat brain was reduced by up to 70% in the presence of vesamicol and its analogs. The levorotary isomer (−)-4-[¹²³I)HIPP exhibits significant accumulation in the monkey brain, with a half-life of about 9 h. Radioiodinated 5 may therefore be a useful tool for studying cholinergic pathways in the brain.

Disulfide links of the IgG2ak anti-ovarian carcinoma antibody, 5G6.4, were site-specifically biotinylated [≈2 biotins/ IgG2a] using a novel crosslinking procedure using the biotin derivatized ETAC (equilibrium transfer alkylation crosslink reagent) 1a. Complexation of ETAC 1a biotinylated 5G6.4 on a column of immobilized protein A at high dilution, followed by passage of [¹²⁵I]streptavidin, washing and pH change leads to elution of a streptavidin-free product with a molecular mass in the 200–300 kDa range. By contrast, direct mixing with [¹²⁵I]streptavidin rapidly gave larger oligomers of ⪢669 and ≈440–669 kDa molecular mass, respectively. The biodistribution of the 200–300 kDa complex showed significantly diminished liver, kidney and spleen uptake as well as higher blood activity than the 440–669 kDa complex. The methodology represent the first application of ETAC chemistry to disulfide-bond directed biotinylation of antibodies and the synthesis of streptavidin antibody conjugates which minimizes their polymerization.

We have prepared and studied six new analogs of 16α-fluoroestradiol (FES): 17α- and 17β-ethynyl-FES (7 [FEES]and 7a), and the 11β-ethyl (8 and 8a) and 11β-methoxy (9 and 9a) derivatives, novel estrogen receptor-based PET imaging agents. The relative binding affinity (RBA) for the estrogen receptor (ER) versus FES is increased for 7, 9 and 9a but decreased for 7a, 8 and 8a. All six analogs have been labeled in the 16α position with ¹⁸F by the nucleophilic displacement of the corresponding 16β-trifluoromethanesulfonate with nBu₄N¹⁸F. Subsequent ethynylation with lithium trimethylsilylacetylide yielded the FEES analogs (total synthesis time: 120 min; effective specific activity: 200–2400 Ci/mmol). Selective uptake in the uterus was high for [¹⁸F)7, [¹⁸F]8, [¹⁸F]9 and [¹⁸F]9a (% ID/g values at 1 h: 11.2, 12.9, 9.9 and 8.3, respectively), while uptake was effectively blocked by coinjection of an excess of unlabeled estradiol. The FEES analogs, [¹⁸F]7, [¹⁸F]8 and [¹⁸F]9, exhibited the highest selectivity, in terms of target (uterus)-to-blood ratios, ever seen amongst estrogen radiopharmaceuticals, 154, 145 and 169, respectively. The analogs [¹⁸F]7a and [¹⁸F]8a displayed no uptake in the uterus, consistent with their low RBAs. Metabolism studies revealed that most of the uterine activity is unmetabolized while the blood exhibits a rapid and subsequently sustained mixture of metabolites. The muscle shows a metabolic profile intermediate to the uterus and blood. These analogs provide an array of desirable characteristics for the optimal PET imaging of ER-rich target tissues.

Radioiodinated rhodamine-123 (Rh123), potential tumor imaging agent, was injected in mice bearing experimentally-induced tumors to investigate its tissue distribution. Some accumulation of radioactivity was found in tumors; most of it cleared rapidly from the blood after injection. Also, the radioiodinated Rh123 had metabolized to water-soluble species which was excreted in urine and feces.

Unlabeled Rh123, on the other hand, accumulated only marginally in the tumors. However, it was found to accumulate significantly in the heart; as much as seventy times the level in blood at 4 h post-injection. Accumulation of unlabeled Rh123 increased steadily even at 24 h post-injection; whereas, it cleared rapidly from the blood via the kidney.

This finding of selective accumulation of Rh123 in heart could be exploited in synthesizing ¹¹C- and ¹⁸F-labeled Rh123 for use in PET studies of the myocardium.

Heart lipids were extracted by the Folch technique from Langendorff-perfused rat hearts after administration of 15-(p-[¹³¹I]iodophenyl)pentadecanoic acid and 15-(p-[¹²⁵I]iodophenyl)-3-R,S-methylpentadecanoic acid. Techniques utilizing successive high performance liquid chromatographic (HPLC) analyses have been developed for the evaluation of the uptake of the tracers into neutral lipids and phospholipids of the rat hearts. Phospholipids were separated on a SiO₂ column eluted with a gradient of acetonitrile/water ($\text{97.5}\text{2.5}$) and acetonitrile/water ($\text{85}\text{15}$) followed by separation of the neutral lipids on a C-18 reversed phase column with a gradient consisting of acetonitrile and 2-propanol/hexane ($\text{60}\text{40}$) containing 1 N H₂SO₄ (5μL/100 mL). Both tracers show the incorporation into the expected major lipid classes.

In an effort to radiolabel antibodies, N-(m-[¹²⁵I]iodophenyl)maleimide (m-[¹²⁵I]IPM) was prepared by the demetallation of an N-[m-tri-(n-butyl)stannylphenyl]maleimide intermediate. The unlabeled intermediate was synthesized in ⩾ 75% yield using a palladium catalyzed reaction of hexabutylditin with m-bromoaniline, followed by reaction with maleic anhydride and ring annulation. All products were confirmed by NMR and elemental analysis. Labeling with ¹²⁵I was carried out in a biphasic mixture containing chloramine-T (radiochemical yield ⩾ 70%). Rabbit IgG modified with the heterobifunctional crosslinking agent N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP) and bovine serum albumin were conjugated with m-[¹²⁵I]IPM (yield: 40 and 80%, respectively). In addition, m-[¹²⁵I]IPM was conjugated to rabbit IgG subunits (HL) in 70% yield. The in vitro stability of the radiolabeled proteins in serum showed < 1% deiodination over 24 h.

Biotinyl-m-[¹²⁵I]iodoanilide (BIA) was synthesized by coupling biotin to m-[¹²⁵I]iodoaniline via a mixed anhydride reaction. m-[¹²⁵I]Iodoaniline was produced from the tin precursor, which was prepared using a palladium catalyzed reaction of hexabutylditin with m-bromoaniline. The radioiodinated BIA derivative is characterized by a stable amide and/or intact ureido group on the biotin molecule; it may thus be a useful carrier for targeting radionuclides to avidin-conjugated antibodies previously localized on tumors.

It is important to know the estrogen receptor rate in breast carcinoma management. Thus, an in vivo and atraumatic method would be very useful. Different ligands have been proposed for this. We present here the specific synthesis of 20E- and 20Z-17α-iodovinyl-11β-methoxyestradiols and their biological characterization as estrogen receptor ligands. The two isomers were analysed by current chemical methods (NMR) and purified by HPLC. We carried out an in vivo study with 21-day-old Swiss mice to compare properties of the two ligands. The 20E-MIVE₂ showed the best affinity for estrogen receptors, the uterus-to-blood ratio was 15-fold higher for the trans derivative. We enhanced the in vivo and in vitro properties of the 20E-MIVE₂: the affinity constant was determined by Scatchard analysis, K_d = 16 × 10⁻¹⁰M, and biodistributions were performed with unlabelled estradiol pre-injection. We concluded that 20E-MIVE₂ can be used for a feasibility study in patients with breast carcinoma.

Residualizing labels for proteins are designed to remain entrapped within cells following uptake and degradation of the carrier protein. In the present work we report the synthesis of a novel residualizing label, N-lactitol-S-([¹⁸F]fluorophenacyl)-cysteamine ([¹⁸F]LCSH, and its use for quantifying the accumulation of low density lipoprotein in tissues in vivo by positron emission tomography (PET). The retention of degradation products in tissues from lipoprotein or from other rapidly catabolized protein pharmaceuticals tagged with [¹⁸F]LCSH reduces leakage of tracer into the plasma compartment. Thus, residualizing labels provide a valuable tool for enhancing signal-to-noise ratios, even during the relatively short interval of PET studies.

The nature of the in vivo defluorination of non-β-oxidizable no-carrier-added ω-[¹⁸F]fluoro long chain fatty acid (LCFA) analogs was studied with the aim of developing PET tracers of LCFA utilization. Extensive defluorination of 15-[¹⁸F]fluoro-3-thia-pentadecanoic acid (FTPA) in mouse was evidenced by radioactivity uptake by bone. [¹⁸F]Fluoride in the blood was verified analytically. Incubations of FTPA in rat-liver homogenates and subcellular fractions thereof showed a strong defluorination process in microsomes which was O₂- and NADPH-dependent. In contrast, defluorination of FTPA was relatively slow in Langendorff perfused rat heart. High bone uptake in mouse was also observed with 14-[¹⁸F]fluoro-13, 13-dimethyl-3-thia-tetradecanoic acid, where gem-dimethyl substitution precludes direct elimination of H¹⁸F. These data indicate that the defluorination of non-β-oxidizable ω-[¹⁸F]fluoro LCFA analogs is primarily governed by cytochrome P-450-mediated ω-oxidation.

Therefore, labeling at the (ω-3) carbon was proposed to provide a more stabile ¹⁸F-label. Defluorination of the (ω-3)-labeled 13 (R,S)-[¹⁸F]fluoro-3-thia-hexadecanoic acid was lower than that of FTPA in mouse and was independent of O₂ and NADPH in vitro. Thus, (ω-3) labeling with ¹⁸F is preferable to ω labeling of non-β-oxidizable LCFA analogs.