Robert N. Hanson

Iododestannylation. Position-specific synthesis of iodotamoxifen

Abstract A procedure has been developed for the synthesis of iodotamoxifen 3 from tamoxifen ( 1 ), an anti-estrogenic agent currently employed in the treatment of breast cancer. Ortho-directed metalation of tamoxifen with sec -butyllithium at −78°C followed by addition of tri- n -butyltin chloride gave the stannyl derivative 2 in 98% isolated yield. Iododestannylation of 2 at 0°C with iodine afforded the desired iodotamoxifen 3 in quantitative yield. The dimethylaminoethoxy group appears to be more strongly activating for ortho metalation than methoxy.

Radiohalodestannylation: Synthesis of 125I-labeled 17α-E-Iodovinylestradiol

Abstract 17α-E-Iodovinylestradiol and its iodine-125-labeled analog were prepared by halodestannylation. The synthesis of the unlabeled compound was achieved from estrone in two steps with an overall yield of 30%. The tributylstannylvinylestradiol intermediate reacted with sodium [ 125 I]iodide (specific activity = 2200 Ci/mmol) in the presence of hydrogen peroxide and acetic acid to give the 17α-E-[ 125 I]iodovinylestradiol in 40–60% yield after isolation by reversed phase column chromatography. The radiochemical purity was greater than 98% and no other u.v. active components could be detected by HPLC. The ease of preparation and isolation of this radioligand suggests that radiohalodestannylation may be the method of choice for this and structurally similar compounds.

Myocardial infarct imaging with technetium-labeled complexes.

Detection of acute myocardial infarction as an area of increased activity has intrigued investigators for some time. Initial attempts with 203Hg-chlormerodrin and 203Hg-fluorescein analogues were successful in man. More recently, however, successful imaging of the acute myocardial infarct has been achieved with several 99mTc complexes. A large group of radiotracers localize in acutely damaged tissue in various models of experimental infarction. From these data, a number of specific structural properties associated with infarct avidity have been identified; these include the presence of mercury and the structural configuration of the organic carrier.

Unsymmetrical selenides from selenocyanates and methyl Grignard

Abstract The addition of methyl Grignard to diethyl acetamido(cyanoselenobenzyl)malonates 3 and 4 at −78° followed by hydrolysis yields the 3-(4-and 3-methylselenophenyl)alanines 1 and 2.

Synthesis and evaluation of novel-N-[2-(bis-aryl-methoxy)ethyl-N'-aralkyl-α,ω-alkanediamines as potent and selective dopamine reuptake inhibitors : SECO analogs of GBR12935 and GBR12909

Abstract A series of analogs of the N-[2-bis arylmethoxy]-N′-phenylpropyl-piperazines GBR12909 and 12935 was synthesized and evaluated as inhibitors of synaptic monoamine transporters. The data indicated that all of the new compounds demonstrated a selectivity for the dopamine transporter compared to the other monoamine transporters with IC50 values approaching 10 nM. The results suggest that the internal piperazine moiety is not required for activity and may be replaced with a more flexible diamine unit.

Preparation and evaluation of radioiodinated phenylpiperazines as adrenomedullary imaging agents

Abstract A series of 1-alkyl-1-methyl-4-phenylpiperazines were radio-odinated and evaluated as potential adrenal imaging agents. The radioiodination proceeded rapidly (0.5 h) with good yields (60–90%) to provide the [ 125 I]iodophenyl-piperazine derivatives. The tissue distribution studies using normal rats indicated that the quarternary amine 1-hydroxyethylmethyl-4-[ 125 I]iodophenylpiperazinium demonstrated the best adrenal uptake and selectivity of the series. The concentration of activity in the adrenals following the administration of this agent remained elevated for 72 h and gave adrenal to nontarget tissue ratios of 6–11. Substantial myocardial uptake and selectivity were also observed for these radiochemicals suggesting their potential use as myocardial imaging agents.

Biodistribution of 59Fe-thiosemicarbazones

The 59Fe-iron(II) chelates of 2-formylpyridine thiosemicarbazone (I), 5-dimethylamino-2-formylpyridine thiosemicarbazone (II), and 5-hydroxy-2-formylpyridine thiosemicarbazone (III) were prepared and their biodistribution determined in normal rats. Early accumulation of these complexes occurred in the liver, muscle and pelt with lesser amounts in the blood, kidneys and other organs. The tissue levels decreased with a 1 to 2-h half-life with the exception of the liver and intestines. The liver level tended to remain constant over the 2-h period. Accumulation in the gut resulting from hepatobiliary excretion increased over the first 60 min and then leveled off. In rats bearing a subcutaneous glioblastoma the uptake of compound I increased during the first 24 h after administration, and tumor to normal tissue ratios of 2 to 3.3 were obtained.

Preparation and biodistribution of a 125I-labeled β-adrenoceptor antagonist bearing a cardioselectivity-enhancing N-substituent

The radiolabeled β -adrenoceptor antagonist 125 I-3-(2-iodophenoxy)-1-[(3,4-dimethoxyphenylethyl)-amino]propan-2-ol (IDP) was synthesized and its biodistribution was determined in normal rats at 15, 60 and 120 min. The tissues with the highest radiopharmaceutical concentration were the lungs, adrenals, kidneys and liver. Uptake in the lungs was approximately 10 times greater than that in the target organ, the heart, which indicates that pharmacologic cardioselectivity for this class of β -anlagonists does not necessarily produce selective uptake in the myocardium.