Organometallic 99mTc-technetium(I)- and Re-rhenium(I)-folate derivatives for potential use in nuclear medicine

Abstract: The folate receptor (FR) is a high affinity membrane protein which is overexpressed on a wide variety of tumor cells, but highly restricted in normal tissues. Therefore folate derivatives labeled with short living isotopes such as 99mTc (γ, t1/2=6 h) or 188Re (β−, t1/2=17 h) could be used for tumor diagnosis and therapy. In this respect there is a great interest to develop organometallic technetium(I) and rhenium(I) modified folate radiopharmaceuticals. For this purpose folic acid was functionalized with a tridentate picolylamine monoacetic acid chelating system. The chelating system was selectively coupled via an aminohexane spacer to the γ- or α-carboxyl group of the glutamate moiety of folic acid to obtain the corresponding γ- or α-folate derivative or – if directly attached to pteroic acid – the pteroate derivative. The derivatives were reacted with the precursor [M(OH2)3(CO)3]+ (M=99mTc, Re) to form uniform organometallic folate complexes under mild reaction conditions. All compounds were chemically characterized by means of NMR, MS, IR and HPLC. The determination of the IC50-values for the PAMA-γ-folate derivative (100 nM) and the corresponding organometallic rhenium complex (110 nM) proved retained receptor binding properties. The radiolabeling with [99mTc(OH2)3(CO)3]+ was achieved in excellent yield (>95%) at low ligand concentration (10−4 M). The cell binding (>45% of total activity) and internalization (>15% of total activity) of all 99mTc-complexes was very high and specificity for the FR was proved by their complete displacement with excess folic acid. The 99mTc-complexes were positively tested for their plasma stability and for the absence of binding to plasma proteins. [Copyright &y& Elsevier]