title: Macrocyclic paramagnetic agents for MRI: Determinants of relaxivity and strategies for their improvement.
abstract: To dissect the contributions to the longitudinal relaxivity (r1) of two commercial contrast agents (CAs), Gd-DOTA and Gd-HP-DO3A, and to synthesize/characterize a novel macrocyclic agent (Gd-Phen-DO3A) having superior r1.
  
  
  
  Longitudinal relaxation rates R1of the CAs in saline with/without human serum albumin (HSA), ionized simulated body fluid (i-SBF), viscous simulated body fluid (v-SBF), and human plasma were measured. Results have been interpreted to evince the main determinants to the observed r1values.
  
  
  
  In v-SBF or in the presence of HSA, r1is enhanced for all complexes, reflecting the viscosity increase and a weak interaction with proteins. The CAs further differentiate in plasma, with a relaxivity increase (versus saline) of approximately 1, 1.5, and 2.5 mM-1s-1for Gd-DOTA, Gd-HPDO3A, and Gd-Phen-DO3A, respectively. R1versus pH curves in i-SBF indicates that prototropic exchange sizably contributes to the relaxivity of Gd-HP-DO3A and Gd-Phen-DO3A.
  
  
  
  The major contributions to r1in the physiological environment have been highlighted, namely, increased viscosity, complex-protein interaction, and prototropic exchange. The control of these terms allows the design of novel macrocyclic structures with enhanced r1as a result of an improved interaction with plasma's macromolecules and the shift of the prototropic exchange to physiological pH. Magn Reson Med 78:1523-1532, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
authors: Bracco Imaging Spa, Bracco Research Center, Via Ribes 5, 10010, Colleretto Giacosa (TO), Italy.|Dipartimento di Fisica, Università degli Studi di Torino, Via Pietro Giuria 1, 10125, Torino (TO), Italy.
authors: Alberto
authors: A
authors: Fringuello Mingo
authors: Bracco Imaging Spa, Bracco Research Center, Via Ribes 5, 10010, Colleretto Giacosa (TO), Italy.
authors: Sonia
authors: S
authors: Colombo Serra
authors: Dipartimento di Biotecnologie Molecolari e Scienze per la salute - Centro di Molecular Imaging, Università degli Studi di Torino, Via Nizza 52, 10126, Torino (TO), Italy.
authors: Simona
authors: S
authors: Baroni
authors: Bracco Imaging Spa, Bracco Research Center, Via Ribes 5, 10010, Colleretto Giacosa (TO), Italy.
authors: Claudia
authors: C
authors: Cabella
authors: Bracco Imaging Spa, Bracco Research Center, Via Ribes 5, 10010, Colleretto Giacosa (TO), Italy.
authors: Roberta
authors: R
authors: Napolitano
authors: Dipartimento di Biotecnologie Molecolari e Scienze per la salute - Centro di Molecular Imaging, Università degli Studi di Torino, Via Nizza 52, 10126, Torino (TO), Italy.
authors: Ivan
authors: I
authors: Hawala
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125, Torino (TO), Italy.
authors: Irene Maria
authors: IM
authors: Carnovale
authors: Bracco Imaging Spa, Bracco Research Center, Via Ribes 5, 10010, Colleretto Giacosa (TO), Italy.
authors: Luciano
authors: L
authors: Lattuada
authors: Bracco Imaging Spa, Bracco Research Center, Via Ribes 5, 10010, Colleretto Giacosa (TO), Italy.
authors: Fabio
authors: F
authors: Tedoldi
authors: Dipartimento di Chimica I.F.M, Università degli Studi di Torino, Via Pietro Giuria 7, 10125, Torino (TO), Italy.
authors: Silvio
authors: S
authors: Aime
mesh_terms: D003287:Contrast Media / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008954:Models, Biological; D009942:Organometallic Compounds / Q000097:blood / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D014783:Viscosity
chemical_list: D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D012709:Serum Albumin; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate
keywords: GBCAs; MRI; protein binding; prototropic exchange; relaxivity; viscosity