Development of a Conjugate of ^99mTc-EC with Aminomethylenediphosphonate in the Search for a Bone Tracer with Fast Clearance from Soft Tissue

Abstract

For the currently used (99m)Tc-labeled diphosphonates such as (99m)Tc-MDP and (99m)Tc-HDP, the required interval of 2.5 to 3 h between injection and the scintigraphic bone imaging is an inconvenience. The present study was set up in an attempt to develop a technetium-99m-labeled diphosphonate with efficient bone uptake and more rapid clearance from blood and soft tissue by renal extraction and excretion so that it would be possible to start imaging as early as 1 h after injection. A conjugate of the new renal tracer agent (99m)Tc-ethylene dicysteine ((99m)Tc-L,L-EC), covalently bound via one of its carboxylates with aminomethylenediphosphonic acid (AMDP), was synthesized in seven steps. EC-AMDP could be labeled easily and efficiently with (99m)Tc at pH > or = 12 and room temperature. Analysis using ion pair reversed phase high performance liquid chromatography showed the formation of a mixture of two main compounds with reproducible relative ratios, which were stable as a function of time. In a baboon, the scintigraphic images obtained with the new agent showed good quality bone scans, with clear visualization of the skeleton and low soft tissue activity at respectively 1 and 2 h after injection.

Preparation and evaluation of a radiogallium complex-conjugated bisphosphonate as a bone scintigraphy agent

“…Thus, we hypothesized that the bone affinity of technetium-99m labeled bisphosphonate would be increased by the design of a bisphosphonate in which the phosphonate groups do not coordinate with technetium-99m. To enable imaging at an earlier time after injection, we and other groups have designed technetium-99m complex-conjugated bisphosphonate compounds based on the concept of bifunctional radiopharmaceuticals [7][8][9][10]. As we expected, some of the novel technetium-99m complex-conjugated Ogawa et al 6/35 bisphosphonate compounds showed superior biodistribution compared with previous compounds.…”

Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

“…Technecium-99m ( 99m Te), the most used radionuclide in biomedical imaging, is able to complex to BPs itself producing not well-defined short-and long-chain coordination polymers with reduced ability to bind to the bone surface. By conjugation of BPs to stronger chelating moieties, such as was L,L-ethylene dicysteine [19] or DTPA [20], 99m Te was coordinated to these ligands leaving BP group unaffected. The corresponding 'bone-seeking' agents showed higher femur-to-blood and femur-to-muscle activity ratios.…”

“…SPECT of bone [19] High femur-to-blood and femurto-muscle activity ratios in vivo Aminomethyl-BP 99m Te-DTPA Amide [20] Dipicolylamine-alendronate 188 Re(CO) 3 Metal coordination [21] Accumulation in areas of high metabolic bone activity while having low soft tissue uptake BP-drug BP-butyric acid Camptothecin Ester Bone cancer treatment [23] Imparting water solubility and HAP-binding affinity to the poorly soluble drug Aminomethyl-BP Diclofenac Ester Bone curing [24] The prodrug demonstrated no gastrointestinal damage as compared to free drug BP-butyric acid Gatifloxacin Acyloxy methyl carbamate [25] The prodrug prevented infection in a rat model…”

A novel 99mTc-labeled dimethyl-substituted zoledronic acid (DMIDP) with improved bone imaging efficiency

“…From the radio-HPLC analysis, the single peak in the HPLC-chromatogram clearly shows the formation of only one complex and excludes the possibility of residual Na 99m TcO 4 or other components [23]. Furthermore, according to the HPLC analysis the radiochemical purity of 99m Tc-DMIDP was found to be larger than 98%.…”