First in vivo MRI assessment of a self-assembled metallostar compound endowed with a remarkable high field relaxivity.

{Fe[Gd(2)bpy(DTTA)(2)(H(2)O)(4)](3)}(4-) is a self-assembled, metallostar-structured potential MRI contrast agent, with six efficiently relaxing Gd(3+) centres confined into a small molecular space. Its proton relaxivity is particularly remarkable at very high magnetic fields (r(1) = 15.8 mM(-1) s(-1) at 200 MHz, 37 degrees C, in H(2)O). Here we report the first in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched compound. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small molecular weight contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate ([Gd(DOTA)(H(2)O)](-) = GdDOTA). The metallostar was well tolerated by the animals at the concentrations of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg(-1) body weight; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high-dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg(-1) BW), despite the higher dose of the latter. The high-dose metallostar injection resulted in a greater drop in the spin-lattice relaxation time (T(1)), as calculated from the inversion recovery true fast imaging with steady-state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approximately four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate molecular weight, the metallostar does not function as a blood pool agent. The dynamic gamma scintigraphic studies performed in Wistar rats with the metallostar compound having (153)Sm enrichment also proved the renal elimination pathway. The biodistribution experiments are in full accordance with the MR and scintigraphic imaging. At 15 min post-injection the activity is primarily localized in the urine, while at 24 h post-injection almost all radioactivity is cleared from tissues and organs.

Medicinal chemistry of somatostatin analogs leading to the DTPA and DOTA conjugates of the multi-receptor-ligand SOM230.

The somatostatin field has been a success story in terms of medicinal chemistry and drug discovery offering a variety of therapeutic opportunities. A rational medicinal chemistry approach capitalising on structure activity relationships has led to the discovery of SOM230, a novel, stable cyclohexapeptide somatostatin analog which exhibits multi-receptor binding to human somatostatin receptor (SSTR) subtypes (SSTR 1-5). Recently, we extended this research utilising the hydroxproline urethane extension of SOM230 for the attachment of the chelators DTPA and DOTA, which enable early diagnosis of SSTR positive tumors and radiotherapy.