Reported metabolic patterns in myocardial stunning are not uniform. We investigated relative myocardial perfusion, glucose and fatty acid uptake using a technetium-99 hexakis-2-methoxyisobutyl-isonitrile (MIBI), fluorine-18 2-fluoro-2-deoxyglucose (FDG) and iodine-125 15-(p-iodo-phenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) mixture, in a recently developed transgenic (TR) mouse model which mimics stunned myocardium. Twenty-seven mice – 14 TR and 13 age-matched wild type controls (C) – were divided into four groups: TR-fed, TR-fasted, C-fed and C-fasted. Animals were sacrificed 2 h after injection, tissue samples counted and percent-injected dose/gram tissue (% id/g) calculated for each radioisotope. Tissues were also Folch extracted and 125I incorporation into the various lipid pools (TG, triglycerides; DG, diglycerides; FFA, free fatty acids; PL, phospholipids) was determined by thin-layer chromatography (TLC). The pooled data for each of the four groups (TR-fed vs C-fed and TR-fed vs C-fasted) showed no differences in myocardial blood flow (% MIBI id/g), glucose uptake (% FDG id/g) or fatty acid uptake (% BMIPP id/g). Only minor differences were observed in the incorporation of 125I-BMIPP into the myocardial TG, DG, FFA and PL lipid pools. However, significantly decreased myocardial FDG uptake was observed in a subset of fasted mice – four out of ten TR-fasted mice (3.4% vs 20.5% id/g) and three out of nine C-fasted mice (5.5% vs 30.6% id/g). The transgenic mouse model of stunned myocardium shows normal myocardial perfusion and overall intact myocardial glucose and myocardial fatty acid uptake as determined with clinically applicable radiolabelled analogues. These data are in line with the hypothesis that the contractile inefficiency in stunned myocardium is not linked to metabolic alterations but is associated with an insufficient chemical to mechanical energy coupling.

Purpose. Irradiation of the arterial wall with beta particles has been shown to be effective in inhibiting neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA). In this study, we describe the use of 188W/188Re generators to obtain 188Re (half-life 16.9 h, maximal beta energy of 2.12 MeV) as a new candidate radioisotope for endovascular irradiation. We have evaluated two [188Re]-compounds as candidates for use as solution-based radiation sources that would allow conventional liquid-filled balloon inflation for delivery of radiation to the vessel wall. While balloon rupture at nominal inflation pressures is a very rare event, (<1 per 10,000 at high pressure), radioisotope release could potentially result in significant dose to radiation-sensitive organs. We have thus evaluated the biodistribution, dosimetry, and kinetics of excretion in rats of two 188Re-labeled compounds that are proposed for intravascular therapy.

Guhlke, S.1; Knapp, F. F.2; Zamora, P. O.1,2,3; Sharma, S.3; Beets, A.1; Oetjen, K.1; Palmedo, H.1; Bender, H.1; Sartor, J.1; Bogatzky, J.1; Biersack, H. J.1 Author Information

In this report we describe the synthesis of the Z (cis) isomers of R-l-azabicyclo [2.2.2] oct-3-yl R-and S-{alpha}-hydroxy-{alpha}-(liodo-l-propen-3-yl) - {alpha}-phenylacetate. We also report the results of the in vitro binding assays of the E and Z isomers of the (R, R)- and (R, S)-isomers of IQNP. The Z isomers of IQNP were prepared by there action of (R, R)- or (R, S)-l-azabicyclo [2.2.2] oct-3-yl - {alpha} - hydroxy - {alpha} - phenyl - {alpha} - (l-propyn-3-yl) acetate with tributyltin hydride in HMPA followed by subsequent reaction of the cis tributylstannyl substrate with iodine. In an attempt to increase the yield of the Z isomers, the preparation of the Z isomers of the R-or S-ethyl {alpha}-hydroxy-{alpha}-phenyl-{alpha}-(l-propyn-3-yl)acetate was also investigated under a variety of reaction conditions. Results of the in vitro binding assays demonstrated that although all the isomers showed high affinity for the muscarinic receptor, the E-(R, R)-IQNP isomer had a 100 times greater higher affinity for m{sub 1} and m{sub 3} receptor subtypes as compared to m{sub 2} subtype. We are currently evaluating the in vivo biodistribution properties and pharmocokinetic and autoradiographic analyses of these promising new ligands in detail for potential use of the iodine-123-labeled agents to study muscarinicmore » receptors by Single Photon Emission Computed Tomography (SPECT).« less

The ``IQNP`` agent is an antagonist for the cholinergic-muscarinic receptor. Since the IQNP molecule has two asymmetric centers and either cis or trans isomerism of the vinyl iodide, there are eight possible isomeric combinations. In this report, the systematic synthesis, purification and animal testing of several isomers of radioiodinated ``IQNP`` are reported. A dramatic and unexpected relation between the absolute configuration at the two asymmetric centers and the stereochemistry of the vinyl iodide on receptor specificity was observed. The E-(R)(R) isomer shows specific and significant localization (per cent dose/gram at 6 hours) in receptor-rich cerebral structures (i.e. Cortex = 1.38 + 0.31; Striatum = 1.22 + 0.20) and low uptake in tissues rich in the M{sub 2} subtype (Heart = 0.10; Cerebellum = 0.04). In contrast, the E-(R)(S) isomer shows very low receptor-specific uptake (Cortex = 0.04; Striatum = 0.02), demonstrating the importance of absolute configuration at the acetate center. An unexpected and important observation is that the stereochemistry of the vinyl iodine appears to affect receptor subtype specificity, since the Z-(R,S)(R) isomer shows much higher uptake in the heart (0.56 + 0.12) and cerebellum (0.17 + 0.04). Studies are now in progress to confirm these exciting results in vitro. Progress has also continued during this period with several collaborative programs. The first large-scale clinical tungsten-188/rhenium-188 generator prototype (500 mCi) was fabricated and supplied to the Center for Molecular Medicine and Immunology (CMMI), in Newark, New Jersey, for Phase I clinical trials of rhenium-188-labeled anti CEA antibodies for patient treatment. Collaborative studies are also continuing in conjunction with the Nuclear Medicine Department at the University of Massachusetts where a generator is in use to compare the biological properties of {open_quotes}direct{close_quotes} and {open_quotes}indirect{close_quotes} labeled antibodies.