Great paper by Dr. Brent Wagner
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC13587227/
I saw reference to Dr. Tweedle’s study from 1995, went looking and kept going…
@grok helped with research:
Tweedle studies (date + one line)
Chemistry / development
• 1988 — Wedeking & Tweedle. 153Gd-Gd(DTPA) vs Gd(DOTA) vs free Gd acetate in mice. Free Gd → liver/bone; slow clearance.
• 1989 — US Pat. 4,885,363 (Tweedle et al.). HP-DO3A ligand family → gadoteridol / ProHance.
• 1991 — Tweedle et al. Magn Reson Imaging. Chelates vs endogenous ions (Zn, Cu, Ca): in-vitro transmetallation.
• 1992 — Wedeking, Kumar, Tweedle. Magn Reson Imaging. Seven chelates in mice; acid-dissociation rate predicted 14-day residual Gd in body/liver/femur (r > 0.99).
• 1993 — Wedeking, Kumar, Tweedle. Nucl Med Biol. Free [153Gd]acetate dose map (liver, bone saturation).
• 1993–94 — Kumar/Chang/Tweedle. Inorg Chem. DOTA/DO3A thermodynamics, kinetics, crystal structures.
• 1995 — Tweedle, Wedeking, Kumar. Invest Radiol 30:372–80. Formulated Magnevist, ProHance, Dotarem, Omniscan in mice/rats. 14-day residual: gadoteridol ≈ gadoterate ≤ gadopentetate << gadodiamide. Caldiamide cut Omniscan residual but not to macrocyclic levels.
• 1997 — Tweedle. Eur Radiol. “The ProHance story.” Nonionic + macrocyclic design.
Human / commentary
• 2006 — White, Gibby, Tweedle. Invest Radiol. Human bone ICP-MS after clinical doses: Omniscan >> ProHance.
• 2007 — Tweedle. Br J Radiol. Letter on what “stability” means.
• 2012 — Hao, Runge, Tweedle et al. JMRI. Chemistry and safety review.
• 2015 — Kanal & Tweedle. Radiology. Residual Gd in normal-kidney patients; clinical meaning unknown; choose agent and dose with that in mind.
• 2016 — Tweedle. Magn Reson Imaging. Speciation: chelated vs dissociated Gd.
• 2018 — NIH/ACR/RSNA roadmap (Tweedle co-author). Retention research agenda.
• 2020–23 — Radiology editorials (next-gen agents; Kobayashi cadaver brain/bone/skin; Le Fur rat multi-organ). Same rank order; harm from leftover fraction in normal kidneys still unproven.
Credentials
Michael F. Tweedle, PhD — inorganic/coordination chemist, not a clinician.
Inventor on gadoteridol. Long career at Squibb → Bracco Research USA (1995 paper affiliation). Later Stefanie Spielman Professor of Cancer Imaging, Ohio State University / James Comprehensive Cancer Center; emeritus. High citation count on GBCA chemistry, kinetics, and residual Gd.
Conflicts of interest
Yes, especially 1988–1997.
• Employee of Bracco Research USA when the comparative 153Gd papers were done.
• Inventor of the ligand that became ProHance, the agent his studies ranked as lowest residual.
• 1997 “ProHance story” is company-era product writing.
• Later OSU editorials are academic bylines; he remains the chemist most tied to that product. Contrast research in this field was routinely company-sponsored.
The residual-Gd rank order (linear nonionic highest, macrocyclics lowest) was replicated by others. The conflict is about which product that ranking was built to support, not about whether 153Gd counts existed.
When linears were used vs when macrocyclics arrived
US first approvals (not the 2003 ProHance year on your slide — that is wrong for first US approval).
Linear (open-chain) — first wave, 1988–2008
How that played out in practice
• 1988–mid-1990s: almost all clinical MRI contrast was linear (Magnevist, then Omniscan). That is the window of many older MS protocols and of Tweedle’s rodent work.
• 1992 onward: ProHance available in the US, but Magnevist/Omniscan still dominated volume for years.
• 2006–2010 NSF crisis: FDA restricted Omniscan, Magnevist, OptiMARK in severe renal failure. Use shifted toward macrocyclics + MultiHance.
• 2013+ brain T1 papers: further shift to gadoteridol, gadoterate, gadobutrol.
• EU 2017: linear general-purpose agents largely suspended; US still allows some linears with warnings.
• Today: routine body/CNS MRI in the US is mostly macrocyclic; MultiHance and Eovist remain as specialty linears.
Your handwritten 1–5 look like a personal ranking or order of interest (MultiHance → Gadavist → Dotarem → Eovist), not FDA chronology.
ProHance year on the slide: first US approval was December 1992 (CNS adults), with later supplements (pediatrics, etc.). 2003 on that table is not the original approval year.
More about Dr. Tweedle’s work:
Tweedle’s work on gadolinium chelates runs from the late 1980s (chemistry and early animal biodistribution at Squibb/Bracco) through human bone data, NSF-era editorials, and later commentary on retention vs. risk. He is closely associated with gadoteridol (ProHance), the first nonionic macrocyclic GBCA (US approval 1992).
Core animal / chemistry papers (retention and stability)
• 1988 — Wedeking & Tweedle. Comparison of 153Gd-labeled Gd(DTPA)2−, Gd(DOTA)−, and Gd(acetate) in mice. Early head-to-head of linear vs macrocyclic vs “free” Gd; free Gd deposits heavily in liver and bone and clears slowly.
• 1989 — Tweedle et al. US patent 4,885,363. 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs — the HP-DO3A ligand family that became gadoteridol.
• 1991 — Tweedle, Hagan, Kumar, Mantha, Chang. Magn Reson Imaging. Reaction of gadolinium chelates with endogenously available ions (Zn, Cu, Ca, etc.). In vitro transmetallation / dissociation risk.
• 1992 — Wedeking, Kumar, Tweedle. Magn Reson Imaging. Dissociation of gadolinium chelates in mice: relationship to chemical characteristics. Acid-dissociation rates strongly predicted long-term whole-body, liver, and femur residual 153Gd.
• 1993 — Wedeking, Kumar, Tweedle. Nucl Med Biol. Dose-dependent biodistribution of [153Gd]Gd(acetate)n in mice. Maps where unchelated Gd goes (liver, bone saturation).
• 1993 — Kumar, Chang, Tweedle. Inorg Chem. Equilibrium and kinetic studies of lanthanide complexes of macrocyclic polyaminocarboxylates.
• 1993–1994 — Chang, Francesconi, Kumar, Tweedle et al. Crystal structures and stability of Gd/Y/Fe complexes of DO3A and DOTA.
• 1995 — Tweedle, Wedeking, Kumar. Invest Radiol 30:372–380. Formulated Magnevist, ProHance, Dotarem, and Omniscan in mice and rats. Residual 14-day Gd: gadoteridol ≈ gadoterate ≤ gadopentetate << gadodiamide; caldiamide in Omniscan lowered residual Gd but not to macrocyclic levels.
• 1997 — Tweedle. Eur Radiol. “The ProHance story.” Design rationale: nonionic + macrocyclic (lower osmolality, higher kinetic stability).
Human retention and later commentary
• 2006 — White, Gibby, Tweedle. Invest Radiol. Omniscan vs ProHance residual Gd in human bone (hip surgery samples) by ICP-MS. Linear agent left substantially more Gd in bone after clinical doses.
• 2007 — Tweedle. Br J Radiol. Short letter on what “stability” of Gd chelates actually means.
• 2012 — Hao, Ai, Goerner, Hu, Runge, Tweedle. J Magn Reson Imaging. Review: basic chemistry and safety of MRI contrast agents.
• 2015 — Kanal & Tweedle. Radiology. Editorial: residual/retained Gd in patients with normal renal function; practical implications after Kanda-type brain T1 findings.
• 2016 — Tweedle. Magn Reson Imaging. “Gadolinium deposition: is it chelated or dissociated Gd? How can we tell?” Speciation methods review.
• 2018 — McDonald, Levine, Weinreb, … Tweedle (workshop co-author). Radiology. NIH/ACR/RSNA gadolinium retention research roadmap.
• 2020 — Tweedle. Radiology. “Next-generation MRI contrast agents: still including gadolinium.”
• 2021 — Tweedle. Editorial on Kobayashi et al. human cadaver brain/bone/skin comparison (gadobenate vs gadoteridol); notes higher linear retention but argues clinical toxicity of residual intact chelate or trace ion remains unproven in normal kidneys.
• 2023 — Tweedle. Editorial on Le Fur et al. rat multi-organ ICP-MS/speciation study (gadoteridol lowest among agents tested; kidney cortex highest residual).
Development thread in one line
Linear DTPA-type agents (Magnevist, then Omniscan) → kinetic-stability problem shown in 1988–1995 rodent 153Gd work → macrocyclic HP-DO3A (ProHance) designed and marketed as more inert → later human bone (2006) and brain-signal (2013+) data confirmed the same rank order: linear nonionic > linear ionic ≥ macrocyclic, with gadoteridol often at the low end of residual Gd.
