Technetium-99m Radiopharmaceuticals for Ideal Myocardial Perfusion Imaging: Lost and Found Opportunities

Abstract

The favorable nuclear properties in combination with the rich coordination chemistry make technetium-99m the radioisotope of choice for the development of myocardial perfusion tracers. In the early 1980s, [99mTc]Tc-Sestamibi, [99mTc]Tc-Tetrofosmin, and [99mTc]Tc-Teboroxime were approved as commercial radiopharmaceuticals for myocardial perfusion imaging in nuclear cardiology. Despite its peculiar properties, the clinical use of [99mTc]Tc-Teboroxime was quickly abandoned due to its rapid myocardial washout. Despite their widespread clinical applications, both [99mTc]Tc-Sestamibi and [99mTc]Tc-Tetrofosmin do not meet the requirements of an ideal perfusion imaging agent due to their relatively low first-pass extraction fraction and high liver absorption. An ideal radiotracer for myocardial perfusion imaging should have a high myocardial uptake; a high and stable target-to-background ratio with low uptake in the lungs, liver, stomach during the image acquisition period; a high first-pass myocardial extraction fraction and very rapid blood clearance; and a linear relationship between radiotracer myocardial uptake and coronary blood flow. Although it is difficult to reconcile all these properties in a single tracer, scientific research in the field has always channeled its efforts in the development of molecules that are able to meet the characteristics of ideality as much as possible. This short review summarizes the developments in 99mTc myocardial perfusion tracers, which are able to fulfill hitherto unmet medical needs and serve a large population of patients with heart disease, and underlines their strengths and weaknesses, the lost and found opportunities thanks to the developments of the new ultrafast SPECT technologies.

Technetium Complexes with an Isocyano-alkyne Ligand and Its Reaction Products

“…The ν(CN) stretch is observed at 2164 cm −1 , which corresponds to a hypsochromic shift with respect + complexes (R = t.butyl and phenyl) with similarly large line widths were observed. 13 The single crystals obtained for [5](BF 4 ) were of sufficient quality for X-ray diffraction, and Figure 4 depicts the molecular structure of the compound, confirming that the CNPh azole ligand is C-bonded. Thus, the structure of the cationic product is similar to those of the cations in mer-[Tc(CO) 3 (CNPh)-(PPh 3 ) 2 ](BF 4 ) and mer-[Tc(CO) 3 (CNt.butyl)(PPh 3 ) 2 ](BF 4 ).…”

“…The shortest Tc−C bond is that to C3, which indicates that the trans-labilization effect due to CO ligands is clearly larger than that due to CNPh azole . The isocyanide ligand in [5](BF 4 ) is linearly bonded. More bond lengths and angles are given as Supporting Information.…”

“…The complexity of the synthesis of appropriate isocyanides sets narrow limits to such efforts, and to the best of our knowledge, there are only a few reports about technetium complexes with specifically substituted isocyanides. Such compounds with ester functionalization have been introduced in the context of the search for myocardial imaging agents ([Tc(CPI) 6 ] + , Chart 1) or as mimics for ω-fatty acids (e.g., [Tc(CO) 5 {CN-(CH 2 ) 10 COOMe}] + , Chart 1). 19,20 Corresponding complexes with chemically more flexible isocyanides are practically unknown.…”

Immediate recruitment of dormant coronary collaterals can provide more than half of normal resting perfusion during coronary occlusion in patients with coronary artery disease

“…Uptake of 99m Tc-sestamibi following balloon deflation could potentially falsely increase the estimation of collateral perfusion. However, <5% of the activity remains in the blood stream at 5 minutes after intravenous injection [21]. Since mean balloon injection time in our study was 5 minutes, this likely had minimal impact on our results.…”

Oldie but Goodie: Is Technetium-99m Still a Treasure Trove of Innovation for Medicine? A Patents Analysis (2000–2022)

“…All these examples are representative of radiopharmaceuticals with limited and defined application fields. At present the 99m Tc-market is still paying more attention to some radiopharmaceuticals which generated a very high income during the past two decades, among them sestamibi (Cardiolite as brand name and the generics available from 2008 Stamicis, Adamibi, MibiSPECT, Technemibi), tetrofosmin (Myoview), and many bone agents (several functionalized diphosphonates). , A total of 10 patents correlated to this class of radiopharmaceuticals, with lost patent protection, whereas all inventions disclosed new improved processes for the preparation of generics of the most widely employed radiopharmaceuticals.…”