alpha-Methylene and glycidic acid analogs of IPPA as potential myocardial imaging agents.

Using organozinc cross-coupling reactions, two radiolabeled analogs of 15-(p-iodophenyl) pentadecanoic acid (IPPA) have been designed and synthesized as potential scintigraphic imaging agents for the heart. Both 15-(4-iodophenyl)-tridecylglycidic acid and 15-(4-iodophenyl)-2-methylene pentadecanoic acid were synthesized and radioiodinated. In tissue biodistribution studies in rats, only the alpha-methylene derivative of IPPA displayed a consistently higher heart to blood ratio and a substantially lower degree of thyroid accumulation than did IPPA alone. With respect to a scintigraphic imaging efficacy, the alpha-methylene analog of IPPA and IPPA itself showed essentially equivalent cardiac imaging profiles in rabbits, with a slight extension in imaging time for the alpha-methylene analog of IPPA.

Biodistribution, metabolism, and excretion of radioiodinated phospholipid ether analogs in tumor-bearing rats.

The phospholipid ether analog, [125I]-1-O-[12-(m-iodophenyl)dodecyl]propanediol-3-phosphocholine (NM-295) was synthesized and evaluated for its ability to visualize tumors. Preliminary studies were performed in rats bearing the Walker 256 carcinosarcoma. Most of the radioactivity was cleared from the animals during the first 24 hours. However, the tumor showed a decreased rate of clearance of radioactivity when compared with non-target tissue. This difference in the clearance rate allowed for excellent images of the tumor at 24 hours. Scintigraphic images compared favorably with other radioiodinated phospholipid ether analogs such as [125I-rac-1-O-[12-(m-iodophenyl)dodecyl]-2-O-methylglycero-3- phosphocholine (NM-294) and [125I]-12-(m-iodophenyl)dodecyl phosphocholine (NM-324). In contrast with the latter two compounds, however, tissue distribution studies revealed that NM-295 cleared at a much faster rate from all tissues, including tumor. In addition, within 24 hours following administration of NM-295, over 70% of the radioactivity was excreted as compared to 50% and 20% for NM-294 and NM-324, respectively. The majority of excreted radioactivity appeared in the urine for all three compounds. Thin-layer chromatography of urine and fecal extracts showed the presence of metabolites only. In contrast, lipid extracts of either liver or tumor demonstrated only the presence of the parent compound. Therefore, these data suggest that in each case it was the parent phospholipid analog that was taken up and retained by the tissues, while the metabolic product(s) was cleared and excreted from the animal.

Comparison of methods for incorporating a radioiodinated residualizing cholesteryl ester analog into low density lipoprotein.

Two different methods were evaluated for incorporating [125I]cholesteryl iopanoate ([125I]CI), a non-hydrolyzable cholesteryl ester analog, into LDL. The first procedure was an organic solvent delipidation-reconstitution procedure (R[125I-CI]LDL) while the second involved incubation of detergent (Tween-20)-solubilized [125I]CI with whole plasma (D[125I-CI]LDL). R[125I-CI]LDL behaved similar to native LDL in vitro, but was markedly different in vivo, apparently due to a heterogeneity in particle size. D[125I-CI]LDL, however, was metabolized normally both in vitro and in vivo. These results, combined with the residualizing nature of [125I]CI, demonstrate that D[125I-CI]LDL is appropriate for tracing LDL uptake in vivo.

Synthesis and evaluation of radioiodinated cholesteryl ethers as lipoprotein probes.

Two novel cholesteryl ether derivatives were synthesized and radioiodinated: (1) [125I]cholesteryl m-iodobenzyl ether (125I-CIBE) and (2) [125I]cholesteryl 12-(m-iodophenyl)dodecyl ether (125I-CIDE). These radioiodinated ethers were incorporated into low-density lipoprotein (LDL) by incubating the compounds (solubilized in saline with Tween-20) with isolated LDL or with whole plasma. Such LDL preparations were taken up by cultured fibroblasts in a receptor-dependent manner similar to that of radioiodinated LDL. Upon injection into guinea pigs, 125I-CIBE-labeled guinea pig LDL cleared from the plasma similarly to radioiodinated guinea pig LDL. The primary sites of 125I-CIBE uptake were the adrenal and the liver, and the compound was stable to both hydrolysis and deiodination over 24 h. In summary, 125I-CIBE and 125I-CIDE, like previously described tritiated cholesteryl ethers, appear to be potentially useful tracers of cholesteryl ester uptake. Moreover, these radioiodinated probes have the advantage of being more easily quantitated in tissue samples as well as being detectable by noninvasive scintigraphic imaging.