Trifunctional^99mTc based radiopharmaceuticals: metal-mediated conjugation of a peptide with a nucleus targeting intercalator

Abstract

The development of molecular imaging agents with multiple functions has become a major trend in radiopharmaceutical chemistry. We present herein the syntheses of trifunctional compounds, combining an acridine orange (AO) based intercalator with a GRP receptor specific bombesin like peptide (BBN). Metal-mediated conjugation of these two functions via the [2 + 1] approach to the third function, the [M(CO)(3)](+) (M = (99m)Tc, Re) moiety, yielded the final trifunctional molecules. The strongly fluorescent acridine orange, a nuclear targeting agent, has been derivatised with 4-imidazolecarboxylate as a bidentate ligand and bombesin with an isonitrile group as a monodentate ligand. For cell and nuclear uptake studies, [Re(L(1)-BBN)(L(2)-Ical)(CO)(3)] type complexes were synthesized and characterized. For radiopharmaceutical purposes, the (99m)Tc analogues have been prepared in a stepwise synthesis. Fluorescence microscopy studies on PC-3 cells, bearing the BBN receptor, showed high and rapid uptake into the cytoplasm. For the bifunctional molecule, lacking the BBN peptide, no internalization was observed.

Rhenium and technetium tricarbonyl complexes of 1,4‐Substituted pyridyl‐1,2,3‐triazole bidentate ‘click’ ligands conjugated to a targeting RGD peptide

“…Of the two ligands conjugated to cRGDfK, the ligand with longer polyethylene glycol spacer (L 2b ‐cRGDfK) demonstrated superior radiolabeling with [ 99m Tc(CO) 3 ] + to give [ 99m Tc(CO) 3 L 2b X] (where X = solvent or pyridine). Future studies will focus on the use of these new bidentate 1,4‐substituted pyridyl‐1,2,3‐triazole ligands with isonitrile co‐ligands in place of pyridine …”

Technetium‐99m radiochemistry for pharmaceutical applications

“…As monodentate ligands, phosphines (P), isocyanides (CNR), and aromatic amines have been used. Examples of bidentate ligands are the (N,O) donors such as 2‐picolinic acid (Figure .6); (O,O) donors of the keto‐enol type, like acetylacetone (Figure .7) or 3‐hydroxypyridone; (S,S) donors such as dithiocarbamate (Figure .8); (N,N) donors, like bipyridine; and (P,P) bisphosphine ligands, like 1,2‐bis(hydroxymethylphosphine)ethane . In [ 99m Tc(CO) 3 (P,P)(H 2 O)] complexes, the third position occupied by water is less reactive to substitutions due to the presence of the two strong π‐acidic phosphines.…”

“…The tracer compounds cannot be characterized due to their small amount. For this, the analogous 99 Tc or nonradioactive rhenium compounds are prepared at the macroscopic scale and characterized spectroscopically. Then, comparative HPLC analysis can be performed (Figure 2), where the tracer ( 99m Tc) and the nontracer ( 99 Tc/Re) complexes are coinjected in the HPLC.…”

“…1 It has ideal nuclear properties for optimal imaging with γ cameras and is used in planar scintigraphy as well as in single photon emission computed tomography. The wide use of 99m Tc is owed to (a) the development of 99 Mo/ 99m Tc generators that allow shipment to nuclear medicine departments worldwide; (b) the development of cold kits, namely, the nonradioactive components that are used for the preparation of 99m Tc radiopharmaceuticals in a convenient and reliable way; and (c) its diverse chemistry that has led to the development of numerous 99m Tc radiopharmaceuticals suitable for various diagnostic procedures (Table 1).…”

“…2 | THE RADIOPHARMACEUTICAL CHEMISTRY OF TECHNETIUM-99m 2.1 | Technetium-99m radiochemistry Technetium-99m is available in the form of pertechnetate ( 99m TcO 4 − ), as a 99 Mo/ 99m Tc generator eluate in normal saline. The preparation of 99m Tc compounds, with the exception of 99m Tc colloids, involves the reduction of the radiometal to form a complex with a suitable ligand.…”