Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Promising Perspectives.

Rhenium-188 (188Re) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify 188Re as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of 188Re from the 188W/188Re generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA) 188Re. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a "theranostic pair." Thus, preparation and targeting of 188Re agents for therapy is similar to imaging agents prepared with 99mTc, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on 188Re-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these 188Re-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of 188Re-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that 188Re represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.

Use of the Oak Ridge National Laboratory tungsten-188/rhenium-188 generator for preparation of the rhenium-188 HDD/lipiodol complex for trans-arterial liver cancer therapy.

This work describes the installation, use, and quality control (QC) of the alumina-based tungsten-188 ((188)W)/rhenium-188 ((188)Re) generators provided by the Oak Ridge National Laboratory (ORNL). In addition, methods used for concentration of the (188)Re-perrhenate bolus and preparation of (188)Re-labeled HDD (4-hexadecyl-2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol) for trans-arterial administration for therapy of nonresectable liver cancer also are described. The (188)W/(188)Re generator has a long useful shelf-life of several months and is a convenient on-site (188)Re production system. (188)Re has excellent therapeutic and imaging properties (T(1/2) 16.9 hours; E(betamax) 2.12 MeV; 155-keV gamma ray, 15%) and is cost effectively obtained on demand by saline elution of the generator. The clinical efficacy of a variety of (188)Re-labeled agents has been demonstrated for several therapeutic applications. Because of the favorable physical properties of (188)Re, several (188)Re-labeled agents are being developed and evaluated for the treatment of nonresectable/refractory liver cancer. (188)Re-labeled HDD has been the most widely studied of these agents for this application and has been introduced into clinical trials at a number of institutions. The trans-arterial administration of (188)Re-labeled agents for treatment of inoperable liver cancer requires use of high-level (1-2 Ci) (188)W/(188)Re generators. The handling of such high levels of (188)Re imposes radiological precautions normally not encountered in a radiopharmacy and adequate care and ALARA (ie, "As Low As Reasonably Achievable") principles must be followed. The ORNL generator provides consistently high (188)Re yields (>75%) and low (188)W parent breakthrough (<10(-3)%) over an extended shelf-life of several months. However, the high elution volumes (20-40 mL for 1-2 Ci generators) can require concentration of the (188)Re bolus by postelution passage through silver cation chloride trapping columns used in the cost-effective tandem cation/anion column system. The silver column removes the high levels of chloride anion as insoluble AgCl, thus allowing subsequent specific trapping of the perrhenate anion on the small (QMA SeaPak) anion column. This method permits subsequent elution of (188)Re-perrhenate with a small volume of saline, providing a very high activity-concentration solution. Because the (188)Re-specific volume-activity concentration continually decreases with time, the tandem system is especially effective method for extending the useful generator shelf-life. Low elution flow rates (<1 mL/min) minimize any high back pressure which may be encountered during generator/tandem column elution when using tightly packed, small-particle-size commercial columns. In-house preparation of silver cation columns is recommended since the chloride trapping capacity is essentially unlimited, it is inexpensive and not limited in availability to any one supplier, and back pressure can be eliminated by the use of larger particles. Methods for the preparation of (188)Re-HDD have been optimized and this agent can be obtained in high yield (80%).

Ligand-activated peroxisome proliferator activated receptor gamma alters placental morphology and placental fatty acid uptake in mice.

The nuclear receptor peroxisome proliferator activated receptor gamma (PPARgamma) is essential for murine placental development. We previously showed that activation of PPARgamma in primary human trophoblasts enhances the uptake of fatty acids and alters the expression of several proteins associated with fatty acid trafficking. In this study we examined the effect of ligand-activated PPARgamma on placental development and transplacental fatty acid transport in wild-type (wt) and PPARgamma(+/-) embryos. We found that exposure of pregnant mice to the PPARgamma agonist rosiglitazone for 8 d (embryonic d 10.5-18.5) reduced the weights of wt, but not PPARgamma(+/-) placentas and embryos. Exposure to rosiglitazone reduced the thickness of the spongiotrophoblast layer and the surface area of labyrinthine vasculature, and altered expression of proteins implicated in placental development. The expression of fatty acid transport protein 1 (FATP1), FATP4, adipose differentiation related protein, S3-12, and myocardial lipid droplet protein was enhanced in placentas of rosiglitazone-treated wt embryos, whereas the expression of FATP-2, -3, and -6 was decreased. Additionally, rosiglitazone treatment was associated with enhanced accumulation of the fatty acid analog 15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid in the placenta, but not in the embryos. These results demonstrate that in vivo activation of PPARgamma modulates placental morphology and fatty acid accumulation.

Direct radiolabeling of monoclonal antibodies with generator-produced rhenium-188 for radioimmunotherapy: labeling and animal biodistribution studies.

The use of 188Re from an alumina-based 188W/188Re generator has been investigated for antibody radiolabeling. It was found that, with simple labeling techniques, 188Re can be used immediately after elution. The direct radiolabeling of intact antibodies with 188Re is described. Lyophilized antibody preparations have been reconstituted with 188Re taken directly from the generator at specific activities of up to 15 mCi of 188Re per mg of antibody. Radiolabeling yields of 90 to 98% have been obtained, with the incorporation rate being dependent upon time and the relative concentrations of the reagents. It was determined that the conjugates were immunoreactive and stable when challenged by serum in vitro, with 188Re-immunoglobulin G showing adequate resistance to reoxidation with no transfer of 188Re to serum protein. 188Re-antibody conjugates were shown to clear from the blood faster than the corresponding 131I-labeled antibody, giving rise to good tumor/nontumor ratios at 24 to 72 h postinjection, while serum samples taken from the animals have shown that the circulating 188Re remained bound to immunoglobulin G. The combination of the technologies of the 188W/188Re generator, the direct labeling methodology, and the use of single-vial lyophilized antibody makes the use of 188Re-radiolabeled monoclonal antibodies a simple and convenient method of cancer radioimmunotherapy with a beta-emitting radionuclide.

Effects of beta(-)-emitting (188)Re balloon in stented porcine coronary arteries: an angiographic, intravascular ultrasound, and histomorphometric study.

BACKGROUND: Restenosis within stents may be prevented by ionizing radiation from an intravascular source. METHODS AND RESULTS: A liquid beta(-) radiation ((188)Re) balloon was evaluated in a randomized and blinded porcine coronary model of stent restenosis. Group A pigs (n=17) received 0,16, 22, or 29 Gy at 0.5-mm depth, followed by stenting. Restenosis was quantified by angiography, ultrasound, and histomorphometry at 30 days. Group B (n=7) was stented first and then treated with 0 or 29 Gy with follow-up at 60 days. There was a measurable effect at 16 Gy, which improved with increasing doses. At 29 Gy, the histological stenotic area was reduced by 67% (22% versus 66% in controls, P<0.001). Radiation after stenting was equally effective; the stenotic area was reduced (21% versus 65%, P<0.001). At 16 Gy, the vessel just distal to the stent was significantly smaller than control vessels because of intimal thickening (P=0.003). Radiated vessels had distinctive histology consisting of neointimal fibrin and reduced smooth muscle cells and matrix (P<0.0001). CONCLUSIONS: (188)Re balloon brachytherapy in porcine coronary arteries results in dose-dependent and injury-independent inhibition of stent restenosis for up to 60 days. Restenosis at the borders of the irradiated zone is a potential limitation and may be related to underdosing. Brachytherapy with the (188)Re balloon appears to be safe and feasible for clinical studies.

Repeated bone-targeted therapy for hormone-refractory prostate carcinoma: tandomized phase II trial with the new, high-energy radiopharmaceutical rhenium-188 hydroxyethylidenediphosphonate.

PURPOSE: We investigated the effect of repeated bone-targeted therapy with rhenium-188 hydroxyethylidenediphosphonate (HEDP) in patients with progressive, hormone-resistant prostate carcinoma and bone pain. The aim of this study was to determine the pain palliation and the antitumor effect of rhenium-188 HEDP treatments. PATIENTS AND METHODS: Sixty-four patients were randomly assigned to one of two groups for radionuclide therapy with rhenium-188 HEDP; patients of group A received a single injection, patients of group B received two injections (interval, 8 weeks). After therapy, patients were followed-up by assessment of pain palliation and clinical outcome until death. RESULTS: In both groups, toxicity was low, with moderate thrombopenia and leukopenia (maximum common toxicity criteria grade of 2). The effectiveness of rhenium-188 HEDP for pain palliation was better in the repeated treatment group (group B), with a response rate and time of response of 92% and 5.66 months, respectively (P =.006 and P =.001). In group B, 11 (39%) of 28 patients had a prostate-specific antigen decrease of more than 50% for at least 8 weeks, compared with two (7%) of 30 patients in the single-injection group (group A). The median times to progression of group A and group B were 2.3 months (range, 0 to 12.2 months) and 7.0 months (range, 0 to 24.1 months), respectively (P =.0013), and the median overall survival times were 7.0 months (range, 1.3 to 36.7 months) and 12.7 months (range, 4.1 to 32.2 months), respectively (P =.043). CONCLUSION: Compared with single-injection therapy, repeated bone-targeted therapy with rhenium-188 HEDP administered to patients with advanced progressive hormone-refractory prostate carcinoma enhanced pain palliation and improved progression-free and overall survival. Larger studies are justified to further evaluate the use of rhenium-188 HEDP.

Accumulation of radioiodinated 15-(p-iodophenyl)-6-tellurapentadecanoic acid in ischemic myocardium during acute coronary occlusion and reperfusion.

The myocardial uptake of 15-(p-iodophenyl)-6- tellurapentadecanoic acid ( TPDA ) was studied in dogs during coronary occlusion and after reperfusion. In eight dogs with a 3 hour occlusion (Group A) with (n = 5) and without (n = 3) 30 minutes of reperfusion, iodine-125 TPDA uptake correlated well with microsphere myocardial blood flow over a wide range of flow levels (n = 111, r = 0.94). In six dogs with a 20 minute occlusion of the left anterior descending coronary artery and 1 hour of reperfusion (Group B), iodine-125 TPDA uptake correlated equally well with myocardial blood flow (n = 37, r = 0.90). There was no difference between the slopes of regression lines for Groups A and B, indicating no release from the myocardium of radioiodinated TPDA . Dual radiolabeling of TPDA was employed in five Group A animals by intravenous injection of iodine-125 TPDA during coronary occlusion and iodine-131 TPDA after reperfusion. In 63 myocardial samples, microsphere reperfusion flow and iodine-131 TPDA uptake were closely correlated (r = 0.91). As with monovalent cations, at myocardial flows higher than control flows, iodine-131 TPDA uptake was flow-limited. It is concluded that: 1) radioiodinated TPDA accurately reveals severely ischemic areas of myocardium without myocardial release of the radionuclide in coronary occlusions lasting 20 to 180 minutes and followed by reperfusion, and 2) double radiolabeled TPDA allows assessment of both occlusion and reperfusion flows. This compound may find an application in the measurement of infarct size and the evaluation of interventional therapies in acute myocardial infarction.

Discovery of rhenium and masurium (technetium) by Ida Noddack-Tacke and Walter Noddack. Forgotten heroes of nuclear medicine.

The history of the early identification of elements and their designation to the Mendeleev Table of the Elements was an important chapter in German science in which Ida (1896-1978) and Walter (1893-1960) Noddack played an important role in the first identification of rhenium (element 75, 1925) and technetium (element 43, 1933). In 1934 Ida Noddack was also the first to predict fission of uranium into smaller atoms. Although the Noddacks did not for some time later receive the recognition for the first identification of technetium-99m, their efforts have appropriately more recently been recognized. The discoveries of these early pioneers are even more astounding in light of the limited technologies and resources which were available during this period. The Noddack discoveries of elements 43 and 75 are related to the subsequent use of rhenium-188 (beta/gamma emitter) and technetium-99m (gamma emitter) in nuclear medicine. In particular, the theranostic relationship between these two generator-derived radioisotopes has been demonstrated and offers new opportunities in the current era of personalized medicine.

[(E)-1-[123I]Iodo-1-penten-5-yl]triphenylphosphonium iodide: convenient preparation of a potentially useful myocardial perfusion agent.

A rapid iodination method has been developed for the synthesis of the new 123I-labeled phosphonium cation [(E)-1-iodo-1-penten-5-yl]triphenylphosphonium iodide by I+ treatment of the corresponding trans-vinylboronic acid. This new model myocardial perfusion agent is obtained after purification in 25-50% yield in less than 1 h. High myocardial uptake (5 min, 2.38% dose/g) with prolonged retention (3 h, 2.21% dose/g) was observed in rats. In addition, heart/blood ratios were high and continued to increase over a 1-day period (5 min, 17:1; 60 min, 23:1; 3 h, 27:1; 1 day, 158:1). In rats, the liver uptake was moderate (5 min, 1.40% dose/g; 60 min; 0.25% dose/g). Excellent myocardial images were obtained in a dog.

Synthesis and evaluation of radioiodinated terminal p-iodophenyl-substituted alpha- and beta-methyl-branched fatty acids.

Methods have been developed for the preparation of terminal p-idophenyl-substituted alpha- and beta-methyl-branched long-chain fatty acids. The syntheses and physical properties of 14-(p-iodophenyl)-2(RS)-methyltetradecanoic acid and 15-p-iodophenyl)-3(RS)-methylpentadecanoic acid are described. The radioiodinated agents are of interest as a result of the expected pronounced uptake and prolonged myocardial retention that may result from the inhibition of fatty acid metabolism. Tissue distribution studies in rats with 14-(p-[125I]iodophenyl)-2(RS)-methyltetradecanoic acid and 15-(p-[125I]iodophenyl)-3(RS)-methylpentadecanoic acid show significant heart uptake and prolonged retention accompanied by low in vivo deiodination and high blood levels. A comparison of the heart uptake of the radioiodinated methyl-branched fatty acids and their unbranched analogues has demonstrated a greater myocardial retention of the methyl-branched fatty acids than the unbranched analogues. These results suggest that the mechanism of myocardial retention results from steric or chemical inhibition of the metabolism of these fatty acids by the presence of the methyl group.

Synthesis and biological evaluation of radiolabeled beta-ruthenocenylalanine.

Carrier-free beta-[103,106Ru] ruthenocenylalanine was prepared from 103, 106RuCl3 by utilizing ( ruthenocenylmethyl )trimethylammonium iodide as the key synthetic intermediate. The amino acid analogue was evaluated as a pancreatic imaging agent, but no selective uptake in the pancreas was observed in either rats or mice.

Potential pancreatic imaging agents. Tellurium-123m labeled DL-alpha-amino-gamma-(phenyltelluro)butyric acid.

This report describes the first successful preparation of a 123mTe-labeled alpha-amino acid as a potential pancreatic imaging agent. Tellurium-123m labeled DL-alpha-amino-gamma-(phenyltelluro)butyric acid was prepared by basic hydrolysis of the radiolabeled 5-[beta-(phenyltelluro)ethyl]hydantoin. The hydantoin was prepared by the reacitron of 123mTe-labeled phenyltellurol, generated by sodium borohydride reduction of diphenyl ditelluride, with 5-(beta-bromoethyl)hydantoin. Tissue distribution studies in rats with the 123mTe-labeled amino acid for periods varying from 30 min to 24 h demonstrated only marginal pancreatic accumulation of radioactivity. The significant result of these studies is that a general synthetic method has been developed for the preparation of 123mTe-labeled amino acids.

Evaluation of the brain-specific delivery of radioiodinated (iodophenyl)alkyl-substituted amines coupled to a dihydropyridine carrier.

To evaluate the potential usefulness of radioiodinated phenylamines attached to dihydropyridine carriers as a means of brain-specific delivery of radiopharmaceuticals, 1-methyl-3-[N-[beta- (4-[125I]iodophenyl)ethyl]carbamoyl]-1,4-dihydropyridine ([125I]-9) and 1-methyl-3-[N-(4-[125I]iodophenyl)carbamoyl]-1,4-dihydropyridine ([125I]-13) have been prepared by dithionite reduction of the corresponding pyridinium precursors, [125I]-8 and [125I]-12, respectively. Formation of 8 involved coupling of (p-aminophenyl)ethylamine with N-succinimidyl (1-methyl-3-pyridinio)formate iodide (4) followed by transformation to the corresponding N-piperidinyl- (6) or (diethylamino)- (7) triazines that were converted to 8 by treatment with HI. Alternatively, 12 was prepared by initial conversion of (4-amino-phenyl)mercuric acetate (10) to 4-iodoaniline (11) by treatment with I2 and then coupling with 4. The radioiodinated quaternary products, 8 and 12, showed low brain uptake and low brain to blood ratios, whereas the dihydropyridine analogues, 9 and 13, showed comparatively good brain uptake and good brain to blood ratios in rats. These data demonstrate that dihydropyridine-coupled radiopharmaceuticals can cross the blood-brain barrier and the technique may be useful for the measurement of cerebral blood perfusion.

Design, synthesis, and evaluation of omega-iodovinyl- and omega-iodoalkyl-substituted methyl-branched long-chain fatty acids.

The synthesis of a new methyl-branched fatty acid, (E)-19-iodo-3(RS)-methyl-18-nonadecenoic acid (19), is described. Methyl branching has been introduced at the 3-position to inhibit beta-oxidation and radioiodide has been attached as a trans-vinyl iodide. Preparation of 19 involved a 15-step sequence of reactions climaxing with formation of the methyl ester 18 by iododestannylation of methyl (E)-19-(tri-n-butylstannyl)-3(RS)-methyl-18-nonadecenoate (17) resulting from the reaction of n-Bu3SnH with methyl 3(RS)-methyl-18-nonadecynoate (16). Methyl branching was introduced at an early stage by Friedel-Crafts acylation of thiophene with 3(RS)-methyl-4-carbomethoxybutanoyl chloride (3) generated from 3-methylglutaric anhydride. The new agent, [125I]-19, showed high myocardial uptake (5 min, 4.89% dose/g; 30 min, 3.32% dose/g), good heart/blood (H/B) ratios (5 min, 5.4/1; 30 min, 4.3/1), and significantly greater myocardial retention in fasted rats than the corresponding straight-chain analogue 19-[125I]-iodo-18-nonadecenoic acid (5 min, 3.52% dose/g, H/B = 4.8/1; 30 min, 1.19% dose/g, H/B = 1.6/1). Excellent myocardial images were obtained in rats after administration of [123I]-19 and confirmed the slow myocardial washout over a 60-min period. These data suggest that 19 is a good candidate for evaluation of heart disease involving aberrations in fatty acid metabolism by use of imaging techniques such as single photon emission computerized tomography (SPECT) where redistribution or washout should be minimized.

Effects of alkyl and aryl substitution on the myocardial specificity of radioiodinated phosphonium, arsonium, and ammonium cations.

Several radioiodinated iodopentenyl-trisubstituted phosphonium, arsonium, and ammonium iodides have been prepared and evaluated in rats to determine the effects of structural variations of the cations on myocardial uptake and retention. The synthesis of (E)-(1-iodo-1-penten-5-yl)-trisubstituted phosphonium, arsonium, and ammonium iodides via the condensation of trisubstituted phosphine, arsine, and amine precursors, respectively, with (E)-1,5-diiodopentene is described. In some cases a second route involved condensation with (E)-1-borono-5-iodo-1-pentene followed by iodination. In the phosphonium series, the compounds triphenyl 1, dicyclohexylphenyl 5, tricyclohexyl 6, and dimethyl-n-octyl 8 were prepared. The triphenylarsonium 10 and triethylammonium 11 compounds were also prepared. The corresponding radioiodinated analogues were prepared and tissue distribution studies performed in rats. The results (percent dose/gram, 30 min) demonstrate that replacement of phosphorus with arsenic (1, 3.99%; 10, 3.17%) or the replacement of the phenyl ring with the cyclohexyl ring system (6, 2.67%) has no apparent effect on heart uptake. In the series of compounds studied, replacement of the cyclic ring system with alkyl groups, however, significantly decreased heart uptake with both the phosphorus (8, 1.95%) and nitrogen agents (11, 1.11%). Gamma camera imaging studies with [123I]-5 and [123I]-8 further substantiated the decreased heart uptake with alkyl substitution and the apparent hepatobiliary clearance of 8.

Synthesis and evaluation of radioiodinated (E)-18-iodo-17-octadecenoic acid as a model iodoalkenyl fatty acid for myocardial imaging.

125I-labeled (E)-18-iodo-17-octadecenoic acid (13) has been prepared and evaluated in rats to determine the myocardial uptake and retention and degree of in vivo deiodination of this model iodovinyl-substituted fatty acid, which contains no structural perturbation to inhibit metabolism. This new agent was prepared by NaI-chloramine-T treatment of (17-carbomethoxyheptadec-1-en-1-yl)boronic acid (11) prepared by catecholborane treatment of methyl 17-octadecynoate (10), followed by basic hydrolysis to the free acid (13). The pivotal substrate, 17-octadecynoic acid (9), was prepared by two new routes. The 125I-labeled acid 13 showed high myocardial uptake (1 h, 1.90-2.28% dose/g) with 45% washout after 2 h but lower heart/blood ratios in comparison to analogues containing the tellurium heteroatom. Deiodination was low for the first 2 h after injection (2 h, 61% dose/g). Excellent myocardial images were obtained in a dog with the 123I-labeled agent.

Synthesis and evaluation of radioiodinated 2-(2(RS)-aminopropyl)-5- iodothiophenes as brain imaging agents.

Methods have been developed for the preparation of 2-(2(RS)-aminopropyl)-5-iodothiophenes. The syntheses and physical properties of 2-(2(RS)-aminopropyl)-5-iodothiophene and N-isopropyl-2-(2(RS)-aminopropyl)-5-iodothiophene are described. The radioiodinated agents are of interest because of the high expected uptake and prolonged brain retention that may result from binding to high-capacity, relatively nonspecific amine binding sites. Radioiodine was introduced into the 5-position of 2-(2(RS)-aminopropyl)-5-iodothiophene and N-isopropyl-2-(2(RS)-aminopropyl)-5-iodothiophene by radioiodination of the corresponding 5-boronic acid or 5-(trimethylstannyl) derivatives. Tissue distribution studies in rats with 2-(2(RS)-aminopropyl)-5-[125I]iodothiophene showed high brain uptake (5 min, 2.77% dose/g; 30 min, 2.51% dose/g) and good brain/blood (B/B) ratios (5 min, 6/1; 30 min 3.8/1. A comparison of the brain uptake of the N-isopropyl derivative with the 2(RS)-aminopropyl analogue demonstrated higher initial brain uptake and brain to blood ratios (5 min, 3.2% dose/g; 10.3/1) but more rapid washout (30 min, 1.37% dose; 2.8/1). These data suggest that radiolabeled 2-(2(RS)-aminopropyl)-5-iodothiophenes are potentially useful agents for cerebral perfusion imaging by single-photon-emission computerized tomography (SPECT).

Synthesis and biological evaluation of 17-[131I]iodo-9-telluraheptadecanoic acid, a potential imaging agent.

A method has been developed for the preparation of terminal halogenated tellurium fatty acids (X-R-Te-R'-COOH). The synthesis and physical properties of 17-bromo- and 17-iodo-9-telluraheptadecanoic acid (17-iodo-9-THDA) are described. The radiohalogenated agents are of interest as a result of their expected pronounced and prolonged heart uptake and potential use for evaluation of regional myocardial fatty acid metabolism. Evaluation in rats indicates that the myocardial uptake of 17-[131I]iodo-9-telluraheptadecanoic acid (17-[131I]iodo-9-THDA) is accompanied by significant in vivo deiodination. A comparison of the heart uptake and deiodination of 17-[131I]iodo-9-THDA and 16-[131I]iodopalmitic acid has demonstrated a close similarity in blood levels of radioactivity and thyroid uptake of radioiodide after administration of these agents to rats. These data suggest that the mechanism of deiodination of terminal radioiodinated alkanoic acids primarily results from direct cleavage of the carbon-iodine bond and not from loss of radioiodine from the final catabolite.

Potential cerebral perfusion agents: synthesis and evaluation of a radioiodinated vinylalkylbarbituric acid analogue.

A new iodinated barbiturate has been prepared. Treatment of 5-chloropentyne and propargyl bromide with diethyl 2-ethyl-2-sodiomalonate (DESM) provided diethyl 2-ethyl-2-(1-pentyn-5-yl)malonate (3) and diethyl 2-ethyl-2-propargylmalonate (4), respectively. Similar condensation of DESM with (E)-(5-iodo-1-penten-1-yl)boronic acid (9) or the reaction of catecholborane with 3 provided diethyl (E)-2-ethyl-2-(1-borono-1-penten-5-yl)malonate (8). The direct sodium iodide-chloramine-T iodination of 8 or the treatment of (E)-1,5-diiodo-1-pentene (10) with DESM provided diethyl (E)-2-ethyl-2-(1-iodo-1-penten-5-yl)malonate (11). The condensation of functionalized malonates 3, 4, and 11 with urea in the presence of a base provided the corresponding barbiturates, 5-ethyl-5-(1-pentyn-5-yl)-(5), 5-ethyl-5-propargyl- (6), and (E)-5-ethyl-5-(1-iodo-1-penten-5-yl)barbituric acid (12), respectively. (E)-6-(Ethoxycarbonyl)-1-iodo-1-octene-6-carboxylic acid (13) was isolated as the hydrolytic byproduct of 11. Compound 13 decarboxylated under vacuum to provide ethyl (E)-1-iodo-1-octene-6-carboxylate (14). The 125I-labeled congeners of 12 and 13 were synthesized in the same manner and evaluated in rats. The barbiturate 12 exhibited significant brain uptake (approximately 1% dose after 5 min), demonstrating that iodinated barbiturates freely cross the intact blood-brain barrier.