Lanthanide(III) Complexes of Bis(phosphonate) Monoamide Analogues of DOTA: Bone-Seeking Agents for Imaging and Therapy

Abstract

Lanthanide complexes of DOTA derivatives 2a (BPAMD) and 2b (BPAPD), having a monoamide pendant arm with a bis(phosphonate) moiety, were comparatively tested for application in MRI, radiotherapy, and bone pain palliation. (1)H, (31)P, and (17)O NMR spectroscopy show that they are nine-coordinated, with one water molecule in the first coordination sphere of the Ln(III) ion. The bis(phosphonate) moieties are not coordinated to the lanthanide and predominantly mono- and diprotonated at physiological pH. The parameters governing the longitudinal relaxivities of the Gd complexes are similar to those of other monoamides of DOTA reported in the literature. Upon adsorption on hydroxyapatite, the relaxivities at 20 MHz and 25 degrees C of Gd-2a and Gd-2b were 22.1 and 11 s(-1) mM(-1), respectively. An in vivo gamma-ray imaging study showed that the (177)Lu complexes of 2a and 2b have a high affinity for bones, particularly for growth plates and teeth with a prolonged retention.

PET/CT imaging of osteoblastic bone metastases with 68Ga-bisphosphonates: first human study

“…A novel DOTA-based bisphosphonate, (4-{[bis-(phosphonomethyl)) carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD) [1,2] The advantages of this new bone imaging PET tracer are the very high target to soft tissue ratios and fast clearance, its ease of use and the generator-based availability of 68 Ga which becomes especially important in these days of 99m Tc shortage.While 18 F-fluoride is adsorbed on bone surface and is related to blood flow, the bisphosphonate [ 68 Ga]BPAMD is taken up also by osteoclasts reflecting the farnesyl diphosphate synthase enzyme dynamics in the HMG-CoA reductase pathway. Since this pathway is mainly responsible for the osteoclastic bone destruction, [ 68 Ga]BPAMD may be superior in osteoclastic lesions.…”

“…A novel DOTA-based bisphosphonate, (4-{[bis-(phosphonomethyl)) carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD) [1,2] The advantages of this new bone imaging PET tracer are the very high target to soft tissue ratios and fast clearance, its ease of use and the generator-based availability of 68 Ga which becomes especially important in these days of 99m Tc shortage.…”

“…A novel DOTA-based bisphosphonate, (4-{[bis-(phosphonomethyl)) carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD) [1,2], was labelled using the 68 Ge/ 68 Ga generator-derived positron emitter 68 Ga [3], resulting in the PET tracer [ 68 Ga]BPAMD.…”

Synthetic Procedures Leading towards Aminobisphosphonates

“…These include the activation of carboxylic groups with N,N'-dicyclohexylcarbodiimide (DCC) [129,130]; the use of previously prepared succinimidate esters to obtain 21 extremely complex fluorescent imaging probes (representative examples of a green fluorescent dye 58 and a red fluorescent dye 59 are shown in Scheme 29) [131]; and N,N'-dicarbonylimidazole, which was used to conjugate pamidronate to pullan (polysaccharide composed of maltotriose units) [132] to obtain a system for bone regeneration. Acylation of aminobisphosphonic acids with small acids, such as acrylic acid [133], chloroacetic acid [134] or succinic acid [135], provided useful substrates for further functionalization of larger molecules, such as macrocycles devised for lanthanide ion complexation, chitosan, and hyaluronan.…”

“…These conjugates were synthesized as bone-specific estrogens in the hope that they will protect elderly women from bone loss resulting from osteoporosis. Acylation of aminobisphosphonic acids with small acids, such as acrylic acid [133], chloroacetic acid [134] or succinic acid [135], provided useful substrates for further functionalization of larger molecules, such as macrocycles devised for lanthanide ion complexation, chitosan, and hyaluronan.…”