R.A. Holmes

99mTc-propylene amine oxime (99mTc-PnAO); a potential brain radiopharmaceutical

Propylene amine oxime (PnAO) forms a neutral lipid soluble complex with 99mTc. 99mTc-PnAO can be prepared by simple reduction of 99mTc-pertechnetate with stannous ion in the presence of excess PnAO in saline at or near neutral pH. This agent will passively penetrate biological membranes including the intact blood-brain barrier (BBB) as evidenced by the high brain uptake observed shortly after IV injection. The first-pass extraction efficiency in baboons was estimated to be 80% at normal blood flow. This agent or a derivatized form of 99mTc-PnAO may be useful in assessment of regional cerebral blood flow (rCBF) in humans.

Labeling of amine ligands with 99mTc in aqueous solutions by ligand exchange

Abstract Cyclam, ethylenediamine (EN) and a linear tetraamine (TA) form structurally similar complexes in high yields when pertechnetate is reduced with Sn(II) in aqueous alkaline solutions. Efficient labeling of these amine ligands is also accomplished by transfer of 99mTc from its complexes with diethylenetriaminepentaacetate (DTPA) and citrate. The labeling yields of cyclam, TA and EN using [99m Tc]DTPA are greater than 95% after standing for 30 min at room temperature in 0.03 M solutions of the amine ligands at pH above 11, but less than 10% at pH below 9. Yields of greater than 90% are obtained using [99mTc]citrate under similar conditions at pH 7 or greater. Ethylenediamine-N,N-diacetic acid (ENDA) also forms a complex with 99mTc that exhibits pH dependent stability characteristics that are the same as those of [99mTc]EN. The labeling efficiency of ENDA with 99mTc as a function of pH is nearly identical to that of the other amine ligands.

The production of 99mTc-labeled conjugated antibodies using a cyclam-based bifunctional chelating agent

A bifunctional chelating agent (BFCA) based on a macrocyclic amine, cyclam, was used to form specifically 99mTc labeled rabbit-anti-HSA-antibodies. This study demonstrates the feasibility of forming a highly stable cyclam-based 99mTc-BFCA with its subsequent conjugation to antibodies.

Stabilization of technetium-99m—d,l-hexamethylpropyleneamine oxime (99mTc—d,l-HMPAO) using gentisic acid

Abstract Technetium-99m- d,l -hexamethylpropyleneamineoxime ( 99m Tc- d,l -HMPAO) is a neutral, lipophilic chelate formed from a kit (Ceretec TM ; Amersham International plc, U.K.) by stannous reduction of 99m TcO − 4 . In vitro stability of this tin-reduced radiopharmaceutical is limited requiring administration ⩽ 30 min following formulation. Gentisic acid (2,5-dihydroxybenzoic acid; GA), an antioxidant and free radical scavenger used to stabilize the low-tin skeletal phosphonate radiopharmaceutical, was employed to stabilize the 99m Tc- d,l -HMPAO kit. GA (1 mM) was shown to stabilize 99m Tc- d,l -HMPAO but its effect was highly pH dependent with optimum utility occurring at or near neutral pH. Biodistribution studies in rats at 15 s and 30 min post injection show no change by the addition of GA.

“bulls-eye” Image of Gallbladder Volvulus

A 79-year-old female was admitted with RLQ abdominal pain for 24 hours. The pain gradually localized in the RUQ prior to admission. Peritoneal signs were noted. Liver function tests were normal. DISIDA hepatobiliary scan revealed a patent common bile duct without visualization of the gallbladder. A

Technetium complexes of pentadentate amine-phenol ligands

Abstract We have synthesized five new pentadentate amine-phenol ligands as part of a study to develop bifunctional chelating agents for labeling antibodies with 99m Tc. These ligands were prepared by condensing various triamine ligands with salicylaldehyde and reducing the Schiff bases obtained to get the amine-phenol ligands. Radiochemical studies of 99m Tc and 99 Tc complexes were performed with the precursor imine-phenols and the amine-phenol ligands. Technetium complexes were prepared at total technetium concentrations of 0.1–100μM at ligand concentrations of 100 μM. Complexation yields and radiochemical purities were estimated by Chromatographie techniques, paper electrophoresis and by solvent extraction into CHCl 3 . Complexation was achieved with both imine- and amine-phenol ligands. The amine-phenol complexes were found to be stable over a period of 24 h. The lipophilicities and stability of the amine-phenol complexes were higher than those of the imine-phenol complexes. Biodistribution studies with two of the amine-phenol complexes were carried out in Sprague-Dawley rats. A large portion of the injected activity was taken up by the liver and the clearance rate of the chelates from blood was slow.

Reversed-phase HPLC of [99mTc]tetraamine complexes

Abstract Radiochemical purity of a variety of cationic [99mTc]tetraamine complexes can be conveniently determined by reversed-phase high performance liquid chromatography (HPLC) using styrene-divinylbenzene as the stationary phase. This reversed-phase HPLC system can also be used to rapidly measure the amount of unreduced [99mTc]pertechnetate in preparations of hydrophylic anionic [99mTc]chelates that are used in clinical nuclear medicine (e.g. [99mTc]DTPA, and methylene diphosphonate).

Technetium complexes of tetradentate chiral amine-phenol ligands

Abstract We have synthesized four amine-phenol ligands by condensing 2-hydroxyacetophenone with appropriate diamines and reducing the Schiff base ligands with NaBH4. The final amine-phenol ligands are a mixture of d, l and meso isomers and were used for complexation studies without any separation of the isomers. Radiochemical studies of 99mTc complexes were done at a total technetium concentration of 0.1–100 μM. Complex yields were measured by TLC, paper electrophoresis and by solvent extraction studies. 99mTc complexes were readily formed with the amine-phenol ligands, and the complexes were neutral, lipophilic and showed very good stability in aqueous solutions. Complexation studies with the imine-phenol ligands were also done. Complexes with the imine-phenol ligands formed in lower yields and were less lipophilic. Biodistribution studies of the 99mTc complexes of the amine-phenol ligands were carried out in Sprague-Dawley rats.

Effect of beta blockade with betaxolol on left ventricular systolic function in chronic stable angina pectoris and left ventricular dysfunction

To assess the effect of beta blockade on left ventricular (LV) performance in patients with LV dysfunction and stable angina pectoris, 18 subjects taking a placebo followed by incremental doses of the cardioselective beta-adrenergic blocking agent betaxolol (5, 10, 20, 40 and 80 mg/day) were studied. The study ended with the achievement of optimal clinical beta blockade (heart rate at rest 50 to 60 beats/min, a 20% or smaller increase in heart rate during stage 1 of symptom-limited treadmill exercise using the modified Bruce protocol). Optimal clinical beta blockade produced a decrease in mean frequency of angina, from 6.8 +/- 1.7 to 0.7 +/- 0.8 episodes per week (p less than 0.0005) and an increase in mean treadmill exercise capacity, from 3.1 +/- 1.7 to 7.7 +/- 2.8 minutes (p less than 0.0005). LV systolic function was assessed at rest and during symptom-limited exercise with radionuclide left ventriculography. Mean LV ejection fraction (EF) during therapy with placebo was 39 +/- 7% at rest and 40 +/- 8% at peak exercise. Mean LVEF during optimal clinical beta blockade was 43 +/- 11% at rest and 45 +/- 10% at peak exercise. Neither of these changes was statistically significant. No patient had clinical or radiographic signs of LV failure. The results suggest that optimal clinical beta blockade with betaxolol, in doses sufficient to significantly reduce the frequency of angina and improve exercise capacity in patients with stable angina pectoris and mild to moderate LV systolic dysfunction, does not cause significant deterioration of LV systolic function or produce LV failure.

Labeling of antibodies with 64Cu using a conjugate containing a macrocyclic amine chelating agent

The conjugation of a model antibody (rabbit-anti-HSA-IgG) with a functionalized derivative of cyclam (1-(3-aminopropyl)-4-methyl-1,4,8,11-tetraazacyclotetradecane) is reported. Coupling of this derivative to the antibodies was accomplished using commercially available heterobifunctional coupling agents. The conjugation technique produced minimal effects on the antibody binding activity. 64Cu complexes with this cyclam derivative have excellent stability in human serum and aqueous solutions containing 1 mM EDTA. The high stability of these Cu-complexes suggests that this system, or other analogous systems, may be useful for production of stable 67Cu-immunotherapeutic agents.