New single photon radiopharmaceuticals for renal scintigraphy

Transcription

1 New single photon radiopharmaceuticals for renal scintigraphy Andrew Taylor, M.D.* Malgorzata Lipowska, Ph.D.* Luigi Marzilli, Ph.D. # *Emory University School of Medicine, Atlanta, GA # Louisiana State University, Baton Rouge, LA

2 1980s: Two radiopharmaceuticals were available for evaluating suspected obstruction I-131 OIH (orthoiodohippurate, hippuran) Tc-99m DTPA

3 1. Bilateral obstruction? 2. Unilateral obstruction? 3. No obstruction?

4

5

6

7

8 Problems with I-131 OIH Image quality poor compared to DTPA Radiation to kidneys: 125 rem Radiation to thyroid: 5 rem Not used in pediatrics

9 Alan Fritzberg, PhD in Bolivia. Austria Peak (5,400 m) in the background. Fritzberg et al. J Nucl Med 1986;27:111

10 First MAG3 Scan

11 First MAG3 scan in a patient

12

13 Goal: To develop a Tc-99m renal tracer with a clearance comparable to OIH. DTPA: 120 ml/min MAG3: 320 ml/min OIH: 600 ml/min

14 Clearance of Tc-99m EC isomers in humans as a percentage of OIH Isomer EC/OIH Protein Binding MAG3 56% LL-EC 70 3% 47 6% DD-EC 82 8% 28 13% DL-EC 40 5% 72 2% Taylor et al. J Nucl Med 38:821, 1997

15

16 99m Tc(VII) Reduction and Cores O 1- Reduction Sn 2+ O Tc [ 99m Tc(V)O] m Tc oxo core most frequently used O 99m Tc O O [ 99m Tc(VII)O 4 ] - Reduction K 2 [H 3 BCO 2 ] H 2 O H 2 O OH 2 Tc CO CO CO + 99m Tc tricarbonyl core new approach * [ 99m Tc(I)(CO) 3 (H 2 O) 3 ] + * R. Alberto et al. J. Am. Chem. Soc., 1998; 31:7987; R. Schibli et al., Eur. J. Nucl. Med., 2002; 29:1529

17 Qualitative size comparison of the organometallic precursor [Tc(H 2 O) 3 (CO) 3 ] + (left) and Tc-MAG 3 (right) based on X-ray analyses. Purple = technetium, red = oxygen, gray = carbon, blue = nitrogen, yellow = sulphur. Hydrogen atoms are omitted. R. Schibli et al., Eur. J. Nucl. Med. (2002) 29:

18 First kit for the preparation of [ 99m Tc(H 2 O) 3 (CO) 3 ] + starting from pertechnetate in saline BC = potassium boranocarbonate, K 2 [H 3 BCO 2 ] R. Schibli et al. Eur. J. Nucl. Med. (2002) 29:

19 First Evaluation of a 99mTc-Tricarbonyl Complex, 99mTc(CO)3(LAN), as Renal Tracer in Humans Isomer Tc-99m/OIH MAG3 56% LL-EC 70 3% DD-EC 82 8% LAN 42 5% Lipowska et al. J Nucl Med 47:1032, 2006

20 Nitrilotriacetic Acid (NTA) Amine and carboxyl donor groups Single product with dangling carboxyl Hydrophilic, favoring tubular transport Dianionic at physiologic ph, similar to MAG3 Lipowska et al: J Nucl Med 2009; 50:

21 In vitro stability of 99m Tc(CO) 3 (NTA) Stable in vitro in a physiological phosphate buffer ph 7.4 at 24 h: No sign of transchelation or decomposition after challenge with excess of cysteine and histidine at 37 C over 4 h

22 Comparison of 99m Tc(CO) 3 (NTA) and 131 I- OIH in Sprague-Dawley rats Constant infusion clearance: Equal to OIH Urine excretion at 10, 60 mins: Equal to OIH Gut activity at 60 min: Less than OIH Lipowska et al: J Nucl Med 2009; 50:

23 Volunteers 9 subjects 6 female, 3 male Mean age: 33.8 (range yrs) 12.4 years;

24 Study protocol Simultaneous injection of 200 uci of I-131 OIH and 2 mci of Tc-99m NTA High energy collimator Studies processed using QuantEM 2.0 software Clearance based on single injection, 2 compartment model with eight blood samples from 3 to 90 minutes Urine excretion at 30 and 180 minutes

25 Safety of NTA Eight human volunteers ingested a single dose of NTA (10 mg) and PE, blood chemistry and urine analysis showed no ill effect (1) On the basis of a 2-year study in rats, Health Canada has determined the acceptable daily dose of NTA in drinking water to be 10 ug/kg/day (2). Administered complex is about 0.2 ug/kg. 1. Budny et al: Toxicol Appl Pharmacol. 1973;25: Health Canada. 1990, available

26

27 % uptake TTP (min) 20 min/max Renogram parameters for whole-kidney ROIs in humans (n = 9) Relative uptake Tmax 20min/max ratio Tc(CO)3(NTA) OIH Tc(CO)3(NTA) OIH Tc(CO)3(NTA) OIH Left Kidney Right Kidney 0 Left Kidney Right Kidney 0 Left Kidney Right Kidney P =

28 TTP (min) 20 min/max Renogram parameters for cortical ROIs (n = 9) Tmax 20 min/max ratio Tc(CO)3(NTA) OIH Tc(CO)3(NTA) OIH Left Cortical Right Cortical 0 Left Cortical Right Cortical P =

29 % ID % ID in Urine at 30 and 180 min after injection Tc(CO)3(NTA) OIH min 180 min

30 Plasma protein and red cells binding in humans (n =9) PPB (%) RBC (%) Tc(CO)3(NTA) OIH Tc(CO)3(NTA) OIH

31 Clearance (ml/min) (n = 9) Tc(CO)3(NTA) OIH

32 Summary 1. NTA image quality: excellent 2. Clearance: equal to OIH 3. 30/90 min urine excretion: equal to OIH 4. Transit time: minimally slower than OIH 5. Red cell binding: less than OIH 6. Plasma protein binding: less than OIH

33 20 min/max Cortical 20 min/max ratio for 99m Tc(CO) 3 (NTA) and 99m Tc-MAG3* Tc(CO)3(NTA) Tc-MAG Left Cortical Right Cortical *Esteves et al: AJR 2006;187:W

34 Camera based clearance (ml/min/1.73m 2 ) for 99m Tc(CO) 3 (NTA) and 99m Tc-MAG3* Tc(CO)3(NTA) Tc-MAG *Esteves et al: AJR 2006;187:W

35 Coming attractions! 1. Better agent than NTA? 2. NTA vs OIH in patients with azotemia 3. NTA vs MAG3 in relevant patient populations -Poor kidney function -Suspected obstruction and azotemia

36 Dr. Taylor END

37

38