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Contrast agent design. Some aspects on the synthesis of water-soluble contrast agents of low osmolality.

Journal of Theoretical Biology 24 (1969): 216–226 T. Almén

Development of nonionic contrast media.

Investigative Radiology 20 (1985): S2–S9 T. Almén

Intravenous chelated gadolinium as a contrast agent in NMR imaging of cerebral tumours.

Lancet i (1984): 484–486

D.H. Carr, J. Brown, G.M. Bydder, H.-J. Weinmann, U. Speck, D.J. Thomas, I.R. Young

Characteristics of gadolinium-DTPA complex:

a potential NMR contrast agent.

Am J Roentgenology 142 (1984): 619–624

H.-J. Weinmann, R.C. Brasch, W.-R. Press, G.E. Wesbey

Contrast-enhanced NMR imaging: animal studies using gadolinium-DTPA complex.

Am J Roentgenology 142 (1984): 625–630 R.C. Brasch, H.-J. Weinmann, G.E. Wesbey

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Introduction

From the earliest days after the discovery of X-rays, contrast media have been used to investigate the urinary tract [1, 2]. The initial use of bougies and catheters was followed by the injection of radio-opaque material to show the renal tract. For retrograde pyelography, a suspension of bismuth subnitrate was originally used.

The first major advance was made in 1918 when Douglas Cameron of Minnesota recommended the use of sodium and potassium iodide for retrograde pyelography [3]. Following the successful introduction of retrograde pyelography, Alexander von Lichtenberg (Professor of Urology at St. Hedwig’s Hospital in Berlin) under- took extensive laboratory work in an attempt to develop intravenous urography, but without any result. In 1923 a team of workers at the Mayo Clinic described the use of intravenous and oral sodium iodide to visualize the urinary tract [4].

In 1925 and 1926, Arthur Binz and Curt Räth (Professors of Chemistry from the Agricultural College in Berlin) synthesized many organic iodine and arsenical preparations based on the pyridine ring in an attempt to produce an improved drug for the treatment of syphilis and other infections. The pyridine ring is a six- pointed ring made up of five carbon atoms and one nitrogen atom. Linkage to this ring greatly detoxified the arsenic and iodine atoms. Binz and Räth synthesized more than 700 of these compounds. One group of these iodinated pyridine compounds was found to be selectively excreted by the liver and kidneys and was therefore called the “Selectans”. Some of these synthesized pyridine drugs were sent for clinical evaluation for the treatment of gall bladder and kidney infections.

In 1928, Moses Swick (1900-1985), who was working as a urology intern at Mount Sinai Hospital in New York, was awarded the Libman Scholarship encouraging medical research overseas. He went to work with Professor Leopold Lichtwitz at the Altona Krankenhaus in Hamburg, Germany, where he had some success in the treatment of infections with some of the iodinated Selectan drugs. Since these drugs contained iodine and it occurred to Swick that they might be of value in vi- sualizing the renal tract by X-rays. Swick made radiological, chemical and toxico- logical studies in laboratory animals and in patients. The initial studies were encouraging and Swick transferred his work to gain access to the large number of patients at the urological department of Professor Alexander von Lichtenberg at St Hedwig’s Hospital in Berlin. The first successful human intravenous urograms were produced with (non-ionic) N-methyl-5-iodo-2 pyridone (Selectan neutral) but Swick preferred the less toxic, more soluble salt 5 iodo-2-pyridone-N-acetate sodi- um (Uroselectan) which had been patented by Räth in May 1927. This new compound Uroselectan produced excellent quality intravenous urograms with relative- ly little toxicity. Swick and von Lichtenberg presented the work to the Ninth Congress of the German Urological Society in September 1929. Swick presented the first paper based on the animal work but with several excellent-quality human studies exhibiting various disease processes (e.g., hydronephrosis and horseshoe kidney) Von Lichtenberg and Swick together presented the second paper on the human clinical uses with the paper read by von Lichtenberg. The two papers were published in November 1929 in Klinische Wochenschrift [5,6].

Within two years of the introduction of Uroselectan in 1929, Binz and Räth developed two further modifications of the pyridine ring – diodrast (Diodone) and neo-ipax (Uroselectan B, Iodoxyl), each molecule containing two iodine atoms.

Schering Kahlbaum of Berlin supported Binz and Räth in developing these pyridine agents and they became the world’s leading manufacturer of intravascular contrast agents. These compounds were successful and were the standard intravascular and urologic contrast media for 20 years.

A series of changes progressively reduced toxicity. Sodium acetrizoate (Urokon, Diaginol) was introduced clinically in 1952 by Mallinckrodt and was the

386 Chapter 6 Contrast agents

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first tri-iodinated contrast medium [7]. Hoppe and colleagues [8] in 1956 showed that a second acetyl amino- group could be added to the benzene ring at C5 to produce a fully substituted tri-iodinated acid radical and the toxicity was reduced even further. This compound, sodium diatrizoate, was introduced in the mid- 1950s as Urografin (Schering AG, Germany), Renografin (Squibb, USA) and Hypaque (Sterling Drug). Sodium diatrizoate and its derivatives became the standard intravascular contrast agents until the development of the lower osmolar and non-ionic agents in the early 1970s.

In 1959 the Norwegian pharmaceutical company Nyegaard & Co. were accused by Schering of infringing their patent on diatrizoate which Nyegaard thought had not been patented in Norway. Following this, Nyegaard tried to synthesize diatrizoate by another route and developed a new fully substituted tri-iodinated benzene ring compound (metrizoate) which they marketed as Isopaque.

Torsten Almén was a Swedish radiologist working at Malmö and he studied the pharmacology of contrast agents [9]. He thought that the very high osmolality of the then conventional contrast media was responsibility for much of their toxicity.

He taught himself chemistry and suggested reducing the osmolality of contrast media by substituting the non-radio-opaque cation by a non-ionizing radical such as an amide. His paper on this topic was prepared when he was a Research Fellow in Philadelphia in 1968-9. His thesis, which was theoretical and not supported by clinical research, was rejected by radiological journals, but was eventually pub- lished by the Journal of Theoretical Biology in 1969 [10], a journal of which most radiologists were not aware.

Almén’s ideas were rejected by several leading pharmaceutical manufacturers but Hugo Holterman, the research director of Nyegaard, encouraged his team to attempt synthesis of some of Almén’s theoretical molecules.

The research team at Nyegaard & Co. were not fully convinced that Almén’s proposal could be implemented; however, they were willing to try the ideas. Almén also made known his ideas as to how these compounds might be constructed to facilitate water solubility, hydrophilicity and to reduce viscosity.

Less than six months were to elapse between the first meeting of Almén and the Nyegaard research group in June 1968 and the production of the first compound [11]. The team produced 80 different compounds. In November 1969, after biological and pharmacological testing, compound 16 (called “Sweet Sixteen”) was shown to be the most promising and it was marketed as Amipaque (the first low-osmolar contrast medium, LOCM). Amipaque was based on the glucose amide of Isopaque (metrizoate), leading to its generic name, metrizamide. As it contained the glucose radical, metrizamide could not be autoclaved. It was also unstable in solution and therefore it could not be delivered as a pre-packed sterile solution. Because of the complexities of its production, it was expensive and inconvenient to use, being presented as a freeze-dried powder with a diluent. It was, however, a major toxico- logical improvement on all pre-existing water-soluble myelographic and vascular agents, and in the late 1970s it became the internationally recognized agent for myelography, enabling water-soluble myelography to replace oil (Myodil, Pantopaque) myelography. Although it had an advantageous intravascular profile, metrizamide was generally regarded as too expensive and too inconvenient for vascular studies.

A few years later, in the mid-1970s, metrizamide was replaced by the second- generation LOCM iohexol (Omnipaque) and iopamidol (Niopam), which are easi- er to synthesize and therefore much less expensive [12]. They do not contain the glucose radical and can therefore be autoclaved and they are stable in solution.

These two second-generation LOCM were successful and became the agents of choice in spite of their high cost.

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Metrizamide revolutionized contrast agents and marked the boundary between conventional ionic high-osmolar media (HOCM) and modern LOCM. As recorded above, iohexol and iopamidol were the first two second-generation non- ionic LOCM agents to be synthesized.

In order to further reduce the osmolality two molecules of non-ionic monomers have been linked to produce a large non-ionizing molecule containing six atoms of iodine. Such products include Visipaque (iodixanol) and iotrolan (isovist) which are of physiological osmolality at all concentrations [13]. These new agents have additional benefits and are significantly less nephrotoxic [14].

Torsten Almén has reviewed the development of non-ionic contrast media [15].

Development has resulted in agents isotonic with plasma and causing less pain and toxicity. It has been the development of these safe contrast agents that has greatly facilitated the development of modern radiology and interventional radiology in particular.

References

1. Swick, M (1978) Radiographic media in urology, the discovery of excretion urography.

Surgical Clinics of North America 58: 977-994

2. Grainger RG, Thomas AMK (1999) History of the development of radiological contrast agents (1895-1996). In: Dawson P, Cosgrove DO, Grainger RG. Textbook of Contrast Media. Isis, Oxford. Pp3-14

3. Cameron D (1917) Aqueous solutions of potassium & sodium iodides as opaque media in roentgenography. J American Medical Association 70: 754-755

4. Osborne ED, Sutherland CG, Scholl AJ Jr, Rowntree LG (1923) Roentgenology of the urinary tract during excretion of sodium iodide. American Medical Association 80: 368- 373

5. Swick M (1929) Darstellung der Niere und Harnwege in Roentgenbild durch intra- venöse Einbringung eines neuen Kontraststoffes: des Uroselectans. Klinische Wochen- schrift 8: 2087-2089

6. Von Lichtenberg A, Swick M (1929) Klinische Prüfung des Uroselectans. Klinische Wochenschrift 8: 2089-2091

7. Wallingford VH (1953) The development of organic iodide compounds as X-ray contrast media. Journal of American Pharmacological Association (Scientific Edition) 42:

721-728

8. Hoppe JO, Larsen HA, Coulston FJ (1956) Observations on the toxicity of a new uro- graphic contrast medium, sodium 3,5-diacetamido-2, 4, 6 tri-iodobenzoate (Hypaque sodium) and related compounds. Journal of Pharmacological and Experimental Therapeutics 116: 394-403

9. Grainger RG (1982) Intravascular contrast media – the past, the present and the future.

British Journal of Radiology 55: 1-18

10. Almén T (1969) Contrast agent design. Some aspects on the synthesis of water-soluble contrast agents of low osmolality. Journal of Theoretical Biology 24: 216-226

11. Amdam RP, Sogner K (1994) Wealth of contrasts. Oslo: Ad Notam Gyldendal

12. Dawson P, Grainger RG, Pitfield J (1983) The new low-osmolar contrast media: a simple guide. Clinical Radiology 34: 221-226

13. Dawson P, Saini S, Schild H, Niendorf HP, Schlieff R (1994) Continuing progress in contrast agents. Imaging 6: 273-284

14. Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ (2003) Nephrotoxic effects in high-risk patients undergoing angiography. New England Journal of Medicine 348: 491-499

15. Almén T (1985) Development of non-ionic contrast media. Investigative Radiology 20:

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MRI Contrast Media

The relaxation time of the protons (hydrogen nuclei) in water molecules is the physical principle that determines the signal intensity in magnetic resonance imaging (MRI) [1].

The possibility that manganese ions could be used for in vivo relaxation enhancement was first suggested in 1978 by Helena Mendonça-Dias, Paul C.

Lauterbur and Andrew Rudin [2]. They used manganese and an experimental technique involving ligation of the coronary artery. They showed that the ischemic region was clearly delineated by the relaxation rates and manganese concentrations. However, all of the paramagnetic ions are inherently toxic for clinical use and can be administered only in a chelated form.

Schering AG in Berlin was looking at the topic of MRI contrast agents in 1980.

The director of contrast agent research Ulrich Speck asked Hanns-Joachim Weinmann to study paramagnetic compounds in animals at Siemens AG in Erlangen, Germany [3]. The first studies were performed on 19 May 1981. The problem of toxicity was solved by Weinmann and his colleagues in 1981 and they were able to make well-tolerated paramagnetic contrast agents that were based on the metal chelates of manganese or gadolinium [4,5,6]. The first patent was ap- plied for on 24 July 1981. The first commercially developed contrast agent was gadolinium diethylylene triamine penta-acetic acid (Gd-DTPA, gadopentetate) as the dimeglumine salt and was marketed by Schering as Magnevist. This process of chelation results in a rapid renal excretion after administration and removes the toxic effects of the free metal ions. Schering submitted a patent application for Gd- DTPA dimeglumine in July 1981. Weinmann and two associates presented the results of the phase 1 trials with images from the 0.35T super-conducting Magnetom (Siemens) at the Department of Radiology at the Free University of Berlin at the meeting of the Radiological Society of North America in November 1983. The first clinical trials were made in 1983 at the Free University of Berlin under Professor R.

Felix and at the Hammersmith Hospital in London under Professor R. Steiner. In 1984, Dennis H. Carr from the Hammersmith Hospital and Wolfgang Schörner from Berlin published their results [4,7].

Since the late 1980s, Magnevist has been commercially available for clinical use, followed shortly afterwards by Dotarem from Guerbet and ProHance from Bracco. In general clinical practice about 20% of MRI scans require contrast enhancement.

The development of MRI contrast media continues [8]. These new agents may use new principles of contrast enhancement for organ-specific imaging or novel physico-chemical properties to allow the administration of gadolinium at a higher concentration. Blood pool agents are being developed for magnetic resonance angiography. Weinmann surmises that with new molecular biology techniques, tumor-specific agents may become a reality.

References:

1. Weinmann HJ (1999) Gadolinium chelates: physico-chemical properties, formulation and toxicology. In: Dawson P, Cosgrove DO, Grainger RG. Textbook of Contrast Media.

Isis, Oxford. pp 297-318

2. Lauterbur PC, Mendonça-Dias H, Rudin AM (1978) Augmentation of tissue proton spin- lattice relaxation rates by in vivo addition of paramagnetic ions. in: Dutton PO, Leigh J, Scarpa A (eds). Frontiers of Biological Energetics. New York: Academic Press pp 752-759 3. Haën C (2001) Conception of the first magnetic resonance imaging contrast agents: a

brief history. Topics in Magnetic Resonance Imaging 12: 221-230

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4. Carr D, Brown I, Bydder G, Weinmann HJ, Speck U, Thomas DJ, Young IR (1984) Intravenous chelated gadolinium as a contrast agent in NMR imaging of cerebral tumours. Lancet i: 484-486

5. Weinmann HJ, Brasch RC, Press WR, Wesby GE (1984) Characteristics of gadolinium-DT- PA complex: a potential NMR contrast agent. AJR 142: 619-624

6. Brasch RC, Weinmann HJ, Wesbey GE (1984) Contrast-enhanced NMR imaging: animal studies using gadolinium-DTPA complex. Am J Roentgenology 142: 625-630

7. Claussen C, Laniado M, Schörner W, et al. (1985) Gadolinium-DTPA in MR imaging of glioblastomas and intracranial metastases. Am J Neuroradiol 6: 669-674

8. Weinmann HJ (2003) History of MRI contrast media development, accompanied by Magnevist. 15 years of Magnevist, Satellite Symposium: ECR 2003

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Torsten Almén

(born 1931)

Torsten Almén grew up in Ystad on the most southern coast of Sweden in Skåne.

He trained in medicine at the University of Lund in the 1950s and moved to the Department of Diagnostic Imaging at Malmö General Hospital in 1959 and this is where he was to spend most of his working life. He very soon became interested in angiography and observed that ppatients often suffered short lasting pain when the contrast medium was injected by a pressure injector into the abdominal aorta.

Almén wanted to reduce the pain of injection from contrast medium. He recalls being as a boy with his parents at the west coast of Sweden, in Bohuslän and find- ing swimming in the water not much fun because as soon as he opened his eyes they started to smart. He found that the salty water at Bohuslän drew the fluid out of the mucous membranes of my eyes and made them sore. The brackish water around Ystad did not cause his eyes to smart when he opened them. He reasoned that physiological saline solution in the femoral artery did not draw fluid from the endothelium of the vessel and so did not cause pain, whereas the hypertonic contrast medium in the femoral artery was drawing fluid from the endothelium of the vessel and this caused the pain. Therefore “a plasma-isotonic aqueous solution of contrast medium molecules might not cause pain, and should therefore be creat- ed!”

During 1965 and 1966 he made vain attempts to interest a Swedish pharmaceutical company in his idea, but without success. In December 1966 in Malmö he made a dissertation on “An instrument for guiding an angiography catheter” and a few weeks later traveled to the USA to Temple University in Philadelphia and worked closely with a Physiology Department on the effects of contrast medium on the microcirculation.

In 1968 Almén went to Oslo to work with Nyegaard & Co AS and developed the first non-ionic contrast medium Amipaque (metrizamide). He was named as the senior inventor on the patent for Amipaque and he has been co-inventor of several other contrast media patents.

Torsten Almén was awarded the Fernström Great Nordic Prize in 1987 and at the 1989 World Congress of Radiology he was presented with the Antoine Béclère Prize.

Torsten Almén is currently Professor Emeritus of Diagnostic Radiology at Malmö, Sweden.

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Torsten Almén

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Hanns-Joachim Weinmann

Hanns-Joachim Weinmann graduated in General Biology and Genetics at the Free University Hospital of Berlin in 1969. He then went on to attain his PhD in Biology in 1980.

He worked for Schering developing contrast media. Schering has been a key company in the development of radiological contrast media since the earlest days of the iodinated X-ray contrast media. Weinmann submitted a patent application for Gd-DTPA dimeglumine in July 1981 in a project which also involved Ulrich Speck.

Weinmann is currently the head of MRI and X-ray Research at Schering AG in Berlin, Germany and remains at the forefront of contrast media research.

D.H. Carr J. Brown G.M. Bydder

see Chapter 2.10 on page 219

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Robert C. Brasch

(born 1944)

Dr. Brasch was born in St. Louis, Missouri, US, in 1944. He received his bachelor’s degree from Miami University in Oxford, Ohio, and his medical degree from Washington University at St. Louis, Missouri. After an internship at the University Hospital in San Diego, California, he completed a residency in radiology at the University of California, San Francisco, where he was also a fellow and clinical in- structor in paediatric radiology. In 1977 he earned the position of assistant professor in residence in radiology and from 1982 to 1986 held the position of associate professor in residence in radiology and paediatrics.

In 1986 he accepted his present position as professor in residence in radiology and paediatrics with the University of California San Francisco. Since 1981 he has been director of the Center for Pharmaceutical and Molecular Imaging (CPMI) of the same university, where he also is associate chief of paediatric radiology. In addition, Dr. Brasch has worked as a consultant to the Children’s Cancer Study Group since 1980.

Throughout his illustrious career, Dr. Brasch has served on the editorial boards of numerous journals, including Radiology, Magnetic Resonance Imaging, Pediatric Radiology, Clinical MRI, Advances in NMR Contrast, Academic Radiology, and the Journal of Magnetic Resonance Imaging.

An active researcher and prolific writer, Dr. Brasch has published over 250 scientific articles. He dedicates 25 hours or more to research each week and focuses on investigations of cancer microvascular characteristics as defined quantitatively by contrast-enhanced MRI, investigations of wound healing as reflected in contrast-enhanced MRI, and investigations of the immunologic basis of severe ad- verse reactivity to iodinated radiographic contrast media, as well as on the discovery of novel contrast agents for optical imaging. Currently, Dr. Brasch is principal investigator on two competitively reviewed research grants. He is a reviewer for the American Journal of Roentgenology, the American Journal of Cardiology, Pediatrics, and nine other journals. He has delivered over 475 presentations over the past 20 years on various topics in radiology at both national and international scientific events. For 25 years he has welcomed visiting research fellows from around the world and most notably from Europe to join his laboratory team for one or two years to learn the basics and the joy of radiology research.

Dr. Brasch is a member of a variety of international, state and local societies including the American Roentgen Ray Society, the Radiological Society of North America, the Society for Pediatric Radiology, the European Congress of Radiology, and the European Society for Pediatric Radiology. He was awarded the Memorial Award of the Association of University Radiologists (1976), the James Picker Foundation Fellow in Radiology Research (1977), and the Harry Fischer Award of RSNA for excellence in Contrast Media Research (1997). He became Baker Visiting Professor to Australasian Congress in 1984 and Fellow of the American College of Radiology (1989). He was a recipient of the Caffey Award for Research by Society for Pediatric Radiology (1992 and 1997). He served on the editorial boards of Academic Radiology, Magnetic Resonance Imaging, Pediatric Radiology and JMRI. He has served on the organizing committee of the International Contrast Medium Research Symposium since 1981 and held offices

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in many renowned state and local professional organizations. In 2001, Dr. Brasch was awarded honorary membership of the European Society of Pediatric Radiology.

Dr Brasch’s scientific accomplishments and contributions to radiology training in the United States and worldwide are outstanding. In 2004 he was invitated as Honorary Lecturer of the European Congress of Radiology and the European Association of Radiology to present the Marie Curie Honorary Lecture.

In parts excerpted from www.ecr.org

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6 Contrast Agents

6.5 6.4 6.3 6.2 6.1

6 Contrast Agents

Introduction

References

MRI Contrast Media

References:

Torsten Almén

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