Background
Methods
Chemicals
Analytics
Radionuclides
Synthesis of the dimeric bisphosphonates DOTA(MBP)2 and DO2A(PBP)2
DOTA(MBP)2 in ester form (2)
DOTA(MBP)2 (3)
DO2A(PBP)2 in ester form (5)
DO2A(PBP)2 (6)
Radiolabelling with n.c.a. 177Lu and quality control
Animal studies
Ex vivo biodistribution
Metabolite analysis and in vivo stability
SPECT/CT
Statistical analysis
Results
Synthesis
Radiolabelling with n.c.a. 177Lu and quality control
Biodistribution
Organ | [177Lu]citrate | [177Lu]BPAMD | [177Lu]BPAPD | [177Lu]BPPED | [177Lu]NO2APBP
| [177Lu]DO2A(PBP)2
| [177Lu]DOTA(MBP)2
| |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | |
Blood | n.d. | n.d. | 0.90 | 0.42 | 0.84 | 0.07 | 1.30 | 0.20 | 2.08 | 2.83 | 3.35 | 0.33 | 3.98 | 0.40 |
Brain | n.d. | n.d. | 0.04 | 0.01 | 0.05 | 0.02 | 0.04 | 0.01 | 0.04 | 0.01 | 0.09 | 0.01 | 0.13 | 0.03 |
Pancreas | n.d. | n.d. | 0.31 | 0.14 | 1.60 | 1.18 | 0.37 | 0.12 | 0.27 | 0.08 | 0.73 | 0.15 | 0.68 | 0.14 |
Spleen | n.d. | n.d. | 0.37 | 0.35 | 1.27 | 0.94 | 0.39 | 0.05 | 0.23 | 0.03 | 0.60 | 0.13 | 0.78 | 0.10 |
Adrenal gland | n.d. | n.d. | 0.40 | 0.13 | 0.55 | 0.17 | 0.70 | 0.41 | 0.60 | 0.42 | 1.23 | 0.19 | 1.07 | 0.19 |
Kidneys | n.d. | n.d. | 4.53 | 4.01 | 3.61 | 1.81 | 3.09 | 0.48 | 3.08 | 1.14 | 2.87 | 0.29 | 3.10 | 0.54 |
Adipose tissue | n.d. | n.d. | 0.42 | 0.19 | 1.80 | 0.78 | 0.24 | 0.07 | 0.53 | 0.14 | 1.52 | 0.50 | 0.55 | 0.13 |
Muscle | n.d. | n.d. | 0.19 | 0.08 | 0.78 | 0.70 | 0.24 | 0.03 | 0.21 | 0.05 | 0.49 | 0.30 | 0.49 | 0.11 |
Heart | n.d. | n.d. | 0.36 | 0.14 | 0.36 | 0.04 | 0.52 | 0.10 | 0.31 | 0.06 | 1.34 | 0.17 | 1.45 | 0.30 |
Lung | n.d. | n.d. | 0.61 | 0.24 | 0.61 | 0.07 | 0.75 | 0.08 | 0.50 | 0.05 | 1.87 | 0.41 | 2.04 | 0.32 |
Thymus | n.d. | n.d. | 0.29 | 0.11 | 0.30 | 0.06 | 0.38 | 0.08 | 0.22 | 0.04 | 0.76 | 0.09 | 0.93 | 0.14 |
Harderian gland | n.d. | n.d. | 0.36 | 0.13 | 0.37 | 0.10 | 0.40 | 0.12 | 0.35 | 0.08 | 0.95 | 0.23 | 1.12 | 0.16 |
Liver | n.d. | n.d. | 0.26 | 0.11 | 0.39 | 0.08 | 0.48 | 0.12 | 0.29 | 0.12 | 1.07 | 0.15 | 1.13 | 0.39 |
Testes | n.d. | n.d. | 0.25 | 0.07 | 0.28 | 0.03 | 0.36 | 0.01 | 0.32 | 0.05 | 0.24 | 0.02 | 0.30 | 0.03 |
Femur | n.d. | n.d. | 3.36 | 0.63 | 3.43 | 0.44 | 4.16 | 0.35 | 2.67 | 0.04 | 2.11 | 0.22 | 2.31 | 0.15 |
Organ | [177Lu]citrate | [177Lu]BPAMD | [177Lu]BPAPD | [177Lu]BPPED | [177Lu]NO2APBP
| [177Lu]DO2A(PBP)2
| [177Lu]DOTA(MBP)2
| |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | |
Blood | 0.22 | 0.11 | 0.04 | 0.01 | 0.04 | 0.00 | 0.06 | 0.01 | 0.07 | 0.02 | 1.25 | 0.09 | 1.43 | 0.32 |
Brain | 0.06 | 0.01 | 0.01 | 0.00 | 0.01 | 0.00 | 0.01 | 0.01 | 0.01 | 0.01 | 0.04 | 0.01 | 0.05 | 0.01 |
Pancreas | 0.50 | 0.05 | 0.04 | 0.02 | 0.04 | 0.02 | 0.03 | 0.01 | 0.06 | 0.01 | 0.31 | 0.05 | 0.30 | 0.07 |
Spleen | 0.70 | 0.12 | 0.07 | 0.06 | 0.05 | 0.01 | 0.14 | 0.04 | 0.05 | 0.01 | 0.31 | 0.03 | 0.52 | 0.25 |
Adrenal gland | 0.62 | 0.05 | 0.04 | 0.04 | 0.09 | 0.06 | 0.08 | 0.12 | 0.11 | 0.05 | 0.49 | 0.09 | 0.52 | 0.20 |
Kidneys | 1.41 | 0.11 | 0.35 | 0.06 | 0.39 | 0.06 | 0.38 | 0.04 | 0.47 | 0.07 | 1.66 | 0.40 | 1.41 | 0.16 |
Adipose tissue | 0.35 | 0.03 | 0.04 | 0.02 | 0.06 | 0.02 | 0.02 | 0.01 | 0.09 | 0.03 | 0.55 | 0.12 | 0.29 | 0.16 |
Muscle | 0.35 | 0.02 | 0.02 | 0.01 | 0.03 | 0.02 | 0.02 | 0.00 | 0.02 | 0.01 | 0.15 | 0.01 | 0.24 | 0.06 |
Heart | 0.87 | 0.10 | 0.02 | 0.01 | 0.03 | 0.00 | 0.04 | 0.01 | 0.04 | 0.01 | 0.54 | 0.10 | 0.63 | 0.12 |
Lung | 1.13 | 0.13 | 0.07 | 0.01 | 0.06 | 0.00 | 0.08 | 0.02 | 0.07 | 0.01 | 0.89 | 0.12 | 0.89 | 0.13 |
Thymus | 0.53 | 0.09 | 0.08 | 0.04 | 0.06 | 0.02 | 0.03 | 0.01 | 0.06 | 0.01 | 0.39 | 0.05 | 0.37 | 0.10 |
Harderian gland | 9.62 | 5.62 | 0.04 | 0.01 | 0.11 | 0.11 | 0.16 | 0.08 | 0.06 | 0.01 | 0.42 | 0.05 | 0.46 | 0.09 |
Liver | 1.04 | 0.09 | 0.04 | 0.01 | 0.04 | 0.01 | 0.13 | 0.01 | 0.04 | 0.00 | 0.52 | 0.11 | 0.69 | 0.36 |
Testes | 0.42 | 0.03 | 0.03 | 0.01 | 0.02 | 0.01 | 0.03 | 0.00 | 0.03 | 0.01 | 0.28 | 0.03 | 0.33 | 0.04 |
Femur | 4.12 | 0.31 | 4.84 | 0.44 | 4.05 | 0.36 | 5.67 | 0.10 | 3.34 | 0.28 | 4.48 | 0.38 | 5.41 | 0.46 |
Organ | [177Lu]citrate | [177Lu]BPAMD | [177Lu]BPAPD | [177Lu]BPPED | [177Lu]NO2APBP
| [177Lu]DO2A(PBP)2
| [177Lu]DOTA(MBP)2
| |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | |
Blood | n.d. | n.d. | 0.001 | 0.000 | n.d. | n.d. | 0.001 | 0.001 | n.d. | n.d. | n.d. | n.d. | 0.003 | 0.001 |
Brain | n.d. | n.d. | 0.004 | 0.001 | n.d. | n.d. | 0.014 | 0.021 | n.d. | n.d. | n.d. | n.d. | 0.018 | 0.007 |
Pancreas | n.d. | n.d. | 0.006 | 0.001 | n.d. | n.d. | 0.005 | 0.003 | n.d. | n.d. | n.d. | n.d. | 0.067 | 0.019 |
Spleen | n.d. | n.d. | 0.020 | 0.002 | n.d. | n.d. | 0.021 | 0.003 | n.d. | n.d. | n.d. | n.d. | 0.697 | 0.348 |
Adrenal gland | n.d. | n.d. | 0.009 | 0.006 | n.d. | n.d. | 0.033 | 0.011 | n.d. | n.d. | n.d. | n.d. | 0.166 | 0.063 |
Kidneys | n.d. | n.d. | 0.076 | 0.015 | n.d. | n.d. | 0.088 | 0.010 | n.d. | n.d. | n.d. | n.d. | 0.369 | 0.075 |
Adipose tissue | n.d. | n.d. | 0.004 | 0.003 | n.d. | n.d. | 0.004 | 0.004 | n.d. | n.d. | n.d. | n.d. | 0.026 | 0.012 |
Muscle | n.d. | n.d. | 0.136 | 0.107 | n.d. | n.d. | 0.027 | 0.056 | n.d. | n.d. | n.d. | n.d. | 0.024 | 0.003 |
Heart | n.d. | n.d. | 0.006 | 0.001 | n.d. | n.d. | 0.008 | 0.001 | n.d. | n.d. | n.d. | n.d. | 0.099 | 0.024 |
Lung | n.d. | n.d. | 0.008 | 0.001 | n.d. | n.d. | 0.008 | 0.002 | n.d. | n.d. | n.d. | n.d. | 0.117 | 0.045 |
Thymus | n.d. | n.d. | 0.006 | 0.001 | n.d. | n.d. | 0.006 | 0.002 | n.d. | n.d. | n.d. | n.d. | 0.109 | 0.033 |
Harderian gland | n.d. | n.d. | 0.105 | 0.127 | n.d. | n.d. | 0.113 | 0.132 | n.d. | n.d. | n.d. | n.d. | 0.331 | 0.131 |
Liver | n.d. | n.d. | 0.025 | 0.002 | n.d. | n.d. | 0.027 | 0.003 | n.d. | n.d. | n.d. | n.d. | 0.470 | 0.078 |
Testes | n.d. | n.d. | 0.004 | 0.000 | n.d. | n.d. | 0.004 | 0.001 | n.d. | n.d. | n.d. | n.d. | 0.050 | 0.005 |
Femur | n.d. | n.d. | 5.039 | 0.453 | n.d. | n.d. | 5.197 | 0.435 | n.d. | n.d. | n.d. | n.d. | 7.340 | 1.009 |
Bone/organ | [177Lu]citrate | [177Lu]BPAMD | [177Lu]BPAPD | [177Lu]BPPED | [177Lu]NO2APBP
| [177Lu]DO2A(PBP)2
| [177Lu]DOTA(MBP)2
|
---|---|---|---|---|---|---|---|
Blood | n.d. | 3.7 | 4.1 | 3.2 | 1.3 | 0.6 | 0.6 |
Brain | n.d. | 83.9 | 68.5 | 104.0 | 66.8 | 23.4 | 17.7 |
Pancreas | n.d. | 10.8 | 2.1 | 11.2 | 9.9 | 2.9 | 3.4 |
Spleen | n.d. | 9.1 | 2.7 | 10.7 | 11.6 | 3.5 | 3.0 |
Adrenal gland | n.d. | 8.4 | 6.2 | 5.9 | 4.5 | 1.7 | 2.2 |
Kidneys | n.d. | 0.7 | 0.9 | 1.3 | 0.9 | 0.7 | 0.7 |
Adipose tissue | n.d. | 8.0 | 1.9 | 17.3 | 5.0 | 1.4 | 4.2 |
Muscle | n.d. | 17.7 | 4.4 | 17.3 | 12.7 | 4.3 | 4.7 |
Heart | n.d. | 9.3 | 9.5 | 8.0 | 8.6 | 1.6 | 1.6 |
Lung | n.d. | 5.5 | 5.6 | 5.5 | 5.3 | 1.1 | 1.1 |
Thymus | n.d. | 11.6 | 11.4 | 10.9 | 12.1 | 2.8 | 2.5 |
Harderian gland | n.d. | 9.3 | 9.3 | 10.4 | 7.6 | 2.2 | 2.1 |
Liver | n.d. | 12.9 | 8.8 | 8.7 | 9.2 | 2.0 | 2.0 |
Testes | n.d. | 13.4 | 12.2 | 11.6 | 8.3 | 8.8 | 7.7 |
Bone/organ | [177Lu]citrate | [177Lu]BPAMD | [177Lu]BPAPD | [177Lu]BPPED | [177Lu]NO2APBP
| [177Lu]DO2A(PBP)2
| [177Lu]DOTA(MBP)2
|
---|---|---|---|---|---|---|---|
Blood | 18.7 | 135.6 | 95.1 | 92.9 | 45.8 | 3.6 | 3.8 |
Brain | 65.4 | 613.4 | 513.9 | 419.9 | 254.3 | 111.5 | 104.0 |
Pancreas | 8.2 | 136.4 | 104.9 | 181.6 | 56.7 | 14.5 | 18.0 |
Spleen | 5.8 | 68.2 | 85.7 | 41.0 | 66.0 | 14.2 | 10.4 |
Adrenal gland | 6.6 | 109.6 | 45.8 | 72.5 | 31.4 | 9.1 | 10.4 |
Kidneys | 2.9 | 14.0 | 10.3 | 14.9 | 7.1 | 2.7 | 3.8 |
Adipose tissue | 11.8 | 134.5 | 70.7 | 269.7 | 37.2 | 8.2 | 18.4 |
Muscle | 11.8 | 251.7 | 158.7 | 355.8 | 141.4 | 29.8 | 22.9 |
Heart | 4.7 | 210.1 | 158.7 | 141.1 | 89.0 | 8.2 | 8.6 |
Lung | 3.7 | 69.1 | 62.6 | 67.5 | 46.8 | 5.1 | 6.1 |
Thymus | 7.7 | 58.6 | 70.7 | 212.0 | 59.0 | 11.6 | 14.4 |
Harderian gland | 0.4 | 118.8 | 35.8 | 36.4 | 85.6 | 10.6 | 11.7 |
Liver | 4.0 | 127.5 | 105.4 | 42.3 | 87.0 | 8.6 | 7.8 |
Testes | 9.9 | 179.1 | 199.7 | 185.1 | 113.5 | 15.8 | 16.2 |
Bone/organ | [177Lu]citrate | [177Lu]BPAMD | [177Lu]BPAPD | [177Lu]BPPED | [177Lu]NO2APBP
| [177Lu]DO2A(PBP)2
| [177Lu]DOTA(MBP)2
|
---|---|---|---|---|---|---|---|
Blood | n.d. | 6703 | n.d. | 5123 | n.d. | n.d. | 2639 |
Brain | n.d. | 1405 | n.d. | 365 | n.d. | n.d. | 419 |
Pancreas | n.d. | 851 | n.d. | 1104 | n.d. | n.d. | 110 |
Spleen | n.d. | 257 | n.d. | 246 | n.d. | n.d. | 11 |
Adrenal gland | n.d. | 547 | n.d. | 159 | n.d. | n.d. | 44 |
Kidneys | n.d. | 66 | n.d. | 59 | n.d. | n.d. | 20 |
Adipose tissue | n.d. | 1158 | n.d. | 1231 | n.d. | n.d. | 287 |
Muscle | n.d. | 37 | n.d. | 192 | n.d. | n.d. | 312 |
Heart | n.d. | 885 | n.d. | 653 | n.d. | n.d. | 74 |
Lung | n.d. | 634 | n.d. | 637 | n.d. | n.d. | 63 |
Thymus | n.d. | 787 | n.d. | 933 | n.d. | n.d. | 67 |
Harderian gland | n.d. | 48 | n.d. | 46 | n.d. | n.d. | 22 |
Liver | n.d. | 203 | n.d. | 189 | n.d. | n.d. | 16 |
Testes | n.d. | 1136 | n.d. | 1214 | n.d. | n.d. | 148 |