Search

Introduction Lipophilic delocalized cations accumulate in tumor cell mitochondria due to their higher transmembrane potential. In this work, this strategy was adopted for the development of 99m Tc tumor-targeted imaging agents. Methods Two tridentate ligands containing the triphenylphosphonium cation, L1 (S-cysteinyl) and L2 (N-iminodiacetate) as well as the respective 99m Tc/ReL1 and 99m Tc/ReL2 tricarbonyl complexes were synthesized. The effect of the ligands and the Re complexes on cell growth in U-87 MG glioblastoma cells was assessed. In vitro stability studies and measurement of logP of the 99m Tc tracers was performed. The cellular and mitochondrial uptake of the 99m Tc tracers in U-87 MG cells was evaluated. Biodistribution of 99m TcL1 and 99m TcL2 were performed on SCID mice bearing U-87 MG tumors. Results The ligands L1 , L2 and the Re1 and ReL2 complexes were characterized spectroscopically. Single products 99m TcL1 and 99m TcL2 , >90% stable in rat serum, were obtained. LogP was 0.40±0.14 for 99m TcL1 and −0.02±0.07 for 99m TcL2 . L1 , ReL1 and ReL2 caused no notable cytotoxicity and L2 was found to infer 40% inhibition of cellular growth at 10 −5 M as well as 80% cell death in culture at 10 −4 M. The cell uptake of 99m TcL1 and 99m TcL2 over 4h was 1.26±0.08% and 0.06±0.01% respectively, of which 13.41±3.63% and 18.61±6.19% was distributed in the mitochondria respectively. The initial tumor uptake in mice was found to be >1% ID/g for both 99m Tc tracers. Conclusions In vitro mitochondrial and in vivo tumor targeting was observed, better in 99m TcL1 , however these properties should be optimized in future studies. Advances in Knowledge and Implications for Patient Care: Continuous efforts in this direction may lead to a suitable mitochondrial-targeted 99m Tc imaging agent for tumor detection.

The synthesis, characterization and biological evaluation of two novel 3 + 1 mixed ligand 99mTc-complexes, bearing the 1-(2-methoxyphenylpiperazine) moiety, a fragment of the true 5-HT1A antagonist WAY 100635, is reported. Complexes at tracer level 99mTcO[(CH3CH2)2NCH2CH2N(CH2CH2S)2][o-CH3OC6H4N(CH2CH2)2NCH2CH2S], 99mTc-1, and 99mTcO[((CH3)2CH)2NCH2CH2N(CH2CH2S)2][o-CH3OC6H4N (CH2CH2)2NCH2CH2S], 99mTc-2, were prepared using 99mTc-glucoheptonate as precursor. For structural characterization, the analogous oxorhenium complexes, Re-1 and Re-2, were prepared by ligand exchange reaction using ReOCl3(PPh3)2 as precursor, and characterized by elemental analysis and spectroscopic methods. Complex Re-1 was further characterized by crystallographic analysis. Labeling was performed with high yield (>85%) and radiochemical purity (>90%) using very low ligand concentration. The structure of 99mTc complexes was established by comparative HPLC using the well-characterized oxorhenium analogues as references. In vitro binding assays demonstrated the affinity of these complexes for 5-HT1A receptors (IC50 : 67 and 45 nM for Re-1 and Re-2 respectively). Biological studies in mice showed the ability of 99mTc-1 and 99mTc-2 complexes to cross the intact blood-brain barrier (1.4 and 0.9% dose/g, respectively at 1 min post-inj.). The distribution of these complexes in various regions in rat brain is inhomogeneous. The highest ratio between areas reach and poor in 5-HT1A receptors was calculated for complex Tc-1 at 60 min p.i. (hippocampus/cerebellum = 1.7).

A series of 99m TcO[SN(R)S][S] complexes carrying the 1-(2-methoxyphenyl)piperazine moiety on the tridentate ligand [SN(R)S] was synthesized. For structural characterization and for in vitro binding assays the analogous oxorhenium complexes were prepared. As demonstrated by appropriate competition binding tests in rat hippocampal preparations, all oxorhenium analogues showed affinity for the 5-HT 1A receptor binding sites with IC 50 values at the nanomolar range (IC 50 = 5.8–103 nM). All 99m TcO[SN(R)S]/[S] complexes showed significant brain uptake in rats at 2 min p.i. (0.24–1.31% ID). However, a clear correlation between distribution of radioactivity in the brain and distribution of 5-HT 1A receptors could not be established.

(NO)(H2O)(CO)3] which reacts readily at room temperature with equimolar quantity of cyclohexyl isocyanide to produce the “2 + 1” mixed ligand complex fac-[Re(NO)(isc)(CO)3]. When the reaction takes place with excess of the isocyanide in refluxing toluene for prolonged time, the complexes trans-cis-[Re(NO)(isc)2(CO)2] and [Re(NO)(isc)3(CO)] are isolated by gradual replacement of the carbonyl ligands by isocyanide. All complexes were fully characterized by elemental analysis, spectroscopic methods and X-ray crystallography. These model compounds may prove useful for the development of multimodal complexes bearing more than one pharmacophore for nuclear medicine applications.

Two novel 99m Tc-(SNS/S) complexes: a mono-ester compound carrying an ethyl ester group on the tridentate ligand, 99m TcO[C 2 H 5 OOCCH 2 N(CH 2 CH 2 S) 2 ][SC 6 H 4 CH 3 ], 3, and a diester compound, carrying a second ethyl ester group on the monodentate ligand, 99m TcO[C 2 H 5 OOCCH 2 N(CH 2 CH 2 S) 2 ][SC 6 H 4 COOC 2 H 5 ], 4, were synthesized. The corresponding oxorhenium(V) complexes, 1 and 2 were also synthesized. Enzymatic hydrolysis demonstrated that 3 remains intact after 10 min incubation while 4 is totally converted to an unidentified hydrophilic complex. Tissue distribution data in mice revealed that both complexes, 3 and 4, exhibit significant initial brain uptake (1.42 and 1.01% of injected dose at 5 minutes post injection respectively) and fast blood clearance.

Two novel [99mTc](SNS/S) mixed ligand complexes carrying a pendant ester function on the monothiolate coligand were synthesized. The corresponding oxorhenium and [99gTc]oxotechnetium complexes prepared at the macroscopic level and chemically characterized were used for structure assignment of [99mTc](SNS/S) complexes prepared at the nanomolar level. Enzymatic hydrolysis of the pendant ester group of [99mTc](SNS/S) mixed ligand complexes by esterase was investigated in vitro and compared with that of the ethyl cysteinate dimer, [99mTc]ECD. Preliminary biodistribution data in mice shows that the complexes are lipophilic and exhibit significant initial uptake in rodent brain.

It is generally believed that CONH(CH 2 ) n COOH moiety promotes tubular excretion of organic anions. Recently it was reported that newly developed renal agents, containing the oxotechnetium(V) glycine group, may mimic the carbonyl amide sequence of [ 131 ]I- o -iodohippuric acid. In this study the renal excretion of certain carboxy-cysteamine derivatives is investigated in mice, in the presence of renal tubular transport inhibitor. A similar pattern of renal depression was observed for complexes containing the oxotechnetium glycine sequence, suggesting that this group may satisfy structural parameters for tubular secretion of anionic technetium complexes.

Alkylpiperidinyl and alkylpyrrolidinyl 99mTc-DADT complexes were synthesized and tested for their ability to cross the BBB. Each complex was a mixture of two epimers separated by HPLC. More lipophilic epimers were biologically evaluated in mice, at various time intervals. Similar biodistribution patterns were obtained for both piperidinyl and pyrrolidinyl DADT-complexes. Brain uptake or retention was influenced by the heterocyclic amine introduced into the DADT backbone. Subcellular concentration of selected 99mTc-DADT complexes was more profound in crude nuclear and post-microsomal fractions. Moreover, interaction of 99mTc-2,2,6,6,9,9-hexamethyl-4,7-diaza-4-(3-methylpyrroli dinyl)-ethyl-1,10- decanedithiol with either lipids or microsomes of whole brain was almost unaffected by time. This may suggest that a possible selective site of interaction and metabolism for DADT complexes occurs in brain.

A series of 99mTc-DADT complexes substituted with heterocyclic amines were synthesized and tested for their ability to cross the BBB. Each 99mTc-DADT complex analysed by HPLC was found to consist of two epimers. The more lipophilic epimers were biodistributed in mice. The data demonstrated a significant brain uptake (3-12% dose/g whole brain) and a high lung accumulation (11-85% dose/g) at 2 min p.i. Between the partition coefficients of the technetium complexes, a linear correlation for lung accumulation was observed, while a parabolic curve for brain uptake was found.