Bidentate Ligands

Two monodentate ligands can be combined to one bidentate ligand.According to the chelate effect, the complexes are expected to be even stabler. This is not so crucial since it is almost impossible to replace even monodentate ligands but more importantly, the rate of coordination is expected to be faster. Hence, the ligand concentration to achieve quantitative labelling or complex formation will be lower. In terms of preference, bidentate ligands are similar to mono-dentate ones. Many possible...

Choice of Radionuclide

Some selected metallic radionuclides useful for radiotherapy are shown in Table 1. In general, identifying the most appropriate isotope for radiotherapy is often a difficult task and requires balancing a variety of factors. These include tumor uptake and retention of the radiolabeled BFC-biomolecule (BM) Fig. 1 Schematic presentation of the radiopharmaceutical design. The targeting biomole-cule serves as the vehicle to carry a radionuclide to the receptor site on tumor cells. The radionuclide...

Kit Formulation and Kit Components

Kits are sterile, pyrogen-free, and nonradioactive mixtures, which are dried by lyophilization and stored under nitrogen in glass vials. For target-specific 99mTc radiopharmaceuticals, a kit contains a BFC-BM conjugate and a reducing agent, if necessary. Kit components are often dissolved in a buffer system, and then lyophilized to form a cake. The buffer is often used for pH control, which is extremely important during manufacturing and radiolabeling processes. Sometimes a bulking agent is...

Low Valent Carbonyl Complexes

The chemistry of the precursor fac- ReBr3(CO)3 2- 13,14 was studied with the water-soluble monophosphine 1,3,5-triaza-7-phosphaadamantane (PTA), and with the bisphosphines (HMPE) and (HMPB) 83,84 . The cyclic monophosphine PTA replaces in a stepwise way one or more of the halides in ReBr3(CO)3 2-, yielding ReBr2(CO)3(PTA) - (77), ReBr(CO)3(PTA)2 (78) and Re(CO)3(PTA)3 + (79),which were all characterized by X-ray diffraction analysis. The follow-up of these reactions by 31P NMR techniques...

Molecular Imaging of MDR1 Pgp in Clinical Drug Resistance

Several clinical studies have shown the feasibility of interrogating Pgp transport activity in vivo with imaging cameras commonly available in nuclear medicine facilities 71-73,124-129 . In general, 99mTc-Sestamibi pharmacokinetic data are extracted from tumor images over time and correlated with immuno- histochemical assessment of Pgp expression in the tumor specimen. For example, in a pioneering clinical study, Del Vecchio et al. 124 determined rates of efflux of 99mTc-Sestamibi in 30...

Introduction

Abrams and coworkers 1,2 first reported the use of aromatic hydrazines, including 6-hydrazinonicotinamide (HYNIC), as bifunctional coupling agents (BFCs) for the 99mTc-labeling of polyclonal IgG for imaging inflammation and infection diseases. Since then, the HYNIC technology has successfully been used for the 99mTc-labeling of antibodies 3-8 and small biomolecules (BMs), including chemotactic peptides 9-18 , somatostatin analogs 19-25 ,stealth liposomes 26,27 , antisense oligonucleotides 28-31...

Technetium Oxidation State

While the composition of the ternary ligand 99mTc complexes has been determined via a series of mixed-ligand experiments and by LC-MS at the tracer (99mTc) level, the technetium oxidation state remains unclear. It has been proposed that the technetium oxidation state in the 99mTc tricine complex is +5 55,88 . The oxidation state might change when HYNIC is bonded to the technetium center. Since organohydrazines are good reducing agents, the reaction of HYNIC with 99mTcO4 or an intermediate...

Mixed PO Ligands

The potentially bidentate (o-hydroxyphenyl)diphenylphosphine ligand (PiOH) reacts with MOCl4 - yielding the mono oxocomplex ReOCl3(P1O) - (1) and the bisubstituted MOCl(P1O)2 Mis Tc (2),Re (3) (Scheme 1) 22,23 .Com-plex 2 could also be obtained by a reduction substitution reaction of pertech-netate with P1OH in the presence of HCl, while complex 3 was also synthesized by reacting the anionic trans-dioxo ReO2(P1O)2 - with hydrochloric acid (Scheme 1) 23,24 . Scheme 1 Oxo complexes anchored by...

Organometallic Complexes in Life Science

At a first glance it seems that the special properties of M-C bonds are not involved in biological systems. The well-known coenzyme B12, in which a cobalt- carbon (to adenosyl or methyl) is present, seems rather to be the exception that confirms the rule. In the recent past however, more and more metalloenzymes that contain M-CO fragments have been structurally characterized. These enzymes represent a classical sort of organometallic compound 23-27 . It is probably not just by chance that CO is...

Monodendate Ligands

The incentive of the chemistry of 99(m)Tc(OH2)3(CO)3 + is the fact that it can be considered as a normal aqua-ion with only three available coordination sites. Since the complexes resulting from water substitution are kinetically stable, almost any type of chelator forms coordination compounds with the fac- (m)Tc(CO) 3 + moiety. This is equally true for mono- bi- and tridentate chela-tors regardless of whether the hard-soft condition for ligand and metal centre matches. This behaviour also...

Nitrido Rhenium188 Radiopharmaceuticals

Reduction of the Tetraoxo Rhenium-188 Anion The use of radiolabeled compounds for the treatment of degenerative diseases currently constitutes a rapidly expanding field in nuclear medicine 43 . The basic principle of this therapeutic method involves administration of a radioactive molecule that should incorporate at least one radionuclide emitting high-energy, massive particles such as -electrons or a-particles. After reaching the target tissue, the radiopharmaceutical will deliver its...

Mixed P N X X is O N S Ligands

Aiming their application at the design of stable mixed-ligand complexes of the 3+1 type, Correia and coworkers 56-58 have introduced the new potentially tridentate phosphines (HCyPN2), (HPN2), (H2PNO) and (H2PNS). Using different starting materials and reaction conditions, the coordination chemistry of these heterofunctionalized phosphines was extensively explored (Scheme 12). Scheme 12 Complexes with heterofunctionalized phosphine ligands Scheme 12 Complexes with heterofunctionalized phosphine...

References

Abrams MJ, Juweid M, ten Kate CI, Schwartz DA, Hauser MM, Gaul FE, Fuccello, AJ, Rubin RH, Strauss HW, Fischman AJ (1990) J Nucl Med 31 2022 2. Schwartz DA, Abrams MJ, Hauser MM, Gaul FE, Larsen SK, Rauh D, Zubieta J (1991) Bioconjugate Chem 2 333 3. Ultee ME, Bridger GJ, Abrams MJ, Longley CB, Burton CA, Larsen S, Henson GW, Padmanabhan S, Gaul FE, Schwartz DA (1997) J Nucl Med 38 133 4. Bridger GJ, Abrams MJ, Padmanabhan S, Gaul FE, Larsen S, Henson GW, Schwartz DA, Burton CA, Ultee ME (1996)...

Mixed PN2 X X is P O S Ligands

The potentially tetradentate ligand (H2P2N2) reacts with MO4 - (Mis Tc,Re) or with ReOCl4 -yielding neutral six-coordinate M(V) oxo complexes of the type MO(P2N2)X M is Tc (68), Re (69) (Scheme 16) 68 . Scheme 16 Complexes with Scheme 16 Complexes with Complexes 68 and 69 are six-coordinate with a distorted octahedral coordination geometry, with the equatorial plane being defined by the tetraden-tate P2N2-phosphino-amido and the axial positions being occupied by an oxo group and a monodentate...

Rhenium188 Lipiodol

The complexes 188Re(N)(R2NCS2)2 have been successively utilized for developing the first nitrido Re-188 therapeutic agent for the treatment of hepatocellular carcinoma (HCC) 48,49 . This pathological state is one of the most common cancerous diseases in the world and is particularly frequent in Asiatic and South American areas. It often appears late, and successful surgical resection is difficult or impossible in most patients. Carriers of therapeutic agents that treat hepatoma effectively,...

MTcLabeled Integrin avb3 Receptor Antagonists for Tumor Imaging

The formation of new blood vessels (angiogenesis) is a requirement for malignant tumor growth and metastasis 103-106 . The angiogenic process depends on vascular endothelial cell migration and invasion, regulated by cell adhesion receptors.Integrins are a family of proteins that facilitate cellular adhesion to and migration on the extracellular matrix proteins found in intercellular spaces and basement membranes. They also regulate cellular entry and withdraw from the cell cycle. Integrin avfi3...

Bifunctional Chelators

The use of metallic radionuclides offers many opportunities for designing new radiopharmaceuticals by modifying the coordination environment around the metal with a variety of chelators. The coordination chemistry of the metallic radionuclide will determine the geometry and solution stability of the metal chelate. Different metallic radionuclides have different coordination chemistries, and require BFCs with different donor atoms and ligand frameworks. The metal chelate can significantly impact...

Diastereomers and Chirality Experiments

For the last decade, HPLC has become a routine quality-control technique for 99mTc radiopharmaceuticals. The advantage of radio-HPLC is its capability to determine the RCP for the 99mTc-labeled BM, and to separate different 99mTc species in the kit matrix. It is also a very powerful tool for separation of different isomers, such as diastereomers. For example, HPLC chromatograms of ternary ligand 99mTc complexes 99mTc(HYNIC-BM)(tricine)(L) (L is phos-phines and pyridine analogs) always show two...

Single Photon Emission Computed Tomography Agents for Noninvasive Imaging of PGlycoprotein Transport Activity

99mtc Furifosmin

Increasingly, the choice of systemic therapy for cancer is based on a priori analysis of tumor markers to assess the presence or absence of a molecular pathway or target (such as a key receptor or enzyme activity) for a given therapeutic agent. Identification of tumor markers with diagnostic agents assists in the proper selection of patients most likely to benefit from targeted therapy. Measurement of MDR is one potentially important marker in planning systemic therapy. However, expression of...

Somatostatin Analogs Labeled with Gallium Radionuclides

The first positron-emitting metal radionuclide-labeled somatostatin analog was 68Ga- DFO -OC 36 , where DFO is desferrioxamine B. OC was modified with DFO, which is a chelator that complexes Fe3+ and Ga3+with high stability. The binding affinity of Ga -DFO-OC was tested against 125I-Tyr3 -OC in rat cortex membranes and gave a pIC50 of 8.2. The biodistribution of 67Ga -DFO-OC in normal and in pancreatic islet cell-tumor-bearing rats showed renal clearance and tumor uptake similar to that of...

Reducing Agents

99mTc is obtained from the 99Mo-99mTc generator as 99mTcO- in saline. Since there is no effective chemistry that can be used to attach 99mTcO- to a small BM, the Tc(VII) in 99mTcO4- has to be reduced to a lower oxidation state in order to produce a stable 99mTc-BFC-BM complex. Various reducing agents, including stannous chloride, sodium borohydride, sodium dithionate, sodium dithionite, hydroxamine, formamidine sulfinic acid, dithiothreitol, and water-soluble phosphines, have been used for the...

Protection of the Hydrazine Moiety

The free hydrazine group in the HYNIC-BM conjugate is not stable to oxidation, particularly under basic conditions, and reacts readily with aldehydes or ketones, which are extracted from various plastic and rubber materials. Fig. 6 Stable hydrazones useful for synthesis of ternary ligand 99mTc complexes Fig. 6 Stable hydrazones useful for synthesis of ternary ligand 99mTc complexes This makes it very difficult to maintain the purity and the stability of the HYNIC-BM conjugate during the...

Effect of Coligand on Physical and Biological Properties of 99mTc Radiopharmaceuticals

In ternary ligand technetium complexes, 99mTc(HYNIC-BM)(tricine)(L) ,the coligand may vary from phosphines to pyridine analogues (Fig. 2). The change of coligand will result in a dramatic change in the technetium chelate with respect to the size and charge. For small BMs, the technetium chelate contributes greatly to the overall size and molecular weight of the 99mTc-labeled HYNIC-BM conjugate. The change of coligand may have a significant impact on the physical (hydrophilicity or...

Hydrazinonicotinamide Derivatives as Bifunctional Coupling Agents for 99mTcLabeling of Small Biomolecules

Department of Industrial and Physical Pharmacy, School of Pharmacy and Pharmaceutical Sciences, Purdue University, 575 Stadium Drive,West Lafayette, IN47907-2051, USA lius pharmacy.purdue.edu 1 Introduction 2 99mTc-Labeling of HYNIC-Biomolecule Conjugates Problems and Solutions 119 2.1 Binary Ligand Technetium 2.2 Ternary Ligand Technetium 2.3 Macrocyclic Technetium 3 Protection of the Hydrazine 4 Formulation 4.1 Kit Formulation and Kit Components 4.1.1 Reducing Agents 4.1.2 Buffer Agent 4.1.3...

Antioxidants

99mTc radiopharmaceuticals, when prepared in high quantity, may undergo au-toradiolysis during preparation, release, and storage. Radiolytic degradation imposes serious safety concerns since the radioactivity that is not linked to the targeting BM will accumulate in nontargeted tissues. Decomposition of the ra-diopharmaceutical prior to or during administration will decrease the targeting capability of the BM. Therefore, it is very important to use a stabilizer to minimize autoradiolysis of the...