CA II makes a good PET: Discovering positron emission tomography (PET) probes with high target affinities is challenging. PET probe discovery using in situ click chemistry uses 19F‐bearing fragments ...as 18F surrogates. This ensures that the lead hits and PET probes have equivalent chemical or biological characteristics, making PET probe discovery predictable and reliable.
A new type of inhibitor of tubulin polymerization was discovered based on the 3-aroyl-2-arylbenzo
bthiophene molecular skeleton. The lead compound in this series, ...2-(4′-methoxyphenyl)-3-(3′,4′,5′-trimethoxybenzoyl)-6-methoxybenzo
bthiophene
1, inhibited tubulin polymerization, caused an increase in the mitotic index of CA46 Burkitt lymphoma cells, and inhibited the growth of several human cancer cell lines.
A new type of inhibitor of tubulin polymerization was discovered based on the 3-aroyl-2-arylbenzol
bthiophene molecular skeleton. The lead compound in this series, benzo
bthiophene
1, inhibited tubulin polymerization, caused an increase in the mitotic index of CA46 Burkitt lymphoma cells, and inhibited the growth of several human cancer cell lines.
2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4-(3-(18)F-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamido)butyl)-11-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)acetic acid ((18)F-RGD-K5) has been developed as an α(v)β(3) integrin marker for PET. The purpose of this study was to determine the biodistribution and estimate the radiation dose from (18)F-RGD-K5 using whole-body PET/CT scans in monkeys and humans.
Successive whole-body PET/CT scans were obtained after intravenous injection of (18)F-RGD-K5 in 3 rhesus monkeys (167 ± 19 MBq) and 4 healthy humans (583 ± 78 MBq). In humans, blood samples were collected between the PET/CT scans, and stability of (18)F-RGD-K5 was assessed. Urine was also collected between the scans, to determine the total activity excreted in urine. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on human and monkey biodistributions.
(18)F-RGD-K5 was metabolically stable in human blood up to 90 min after injection, and it cleared rapidly from the blood pool, with a 12-min half-time. For both monkeys and humans, increased (18)F-RGD-K5 uptake was observed in the kidneys, bladder, liver, and gallbladder, with mean standardized uptake values at 1 h after injection for humans being approximately 20, 50, 4, and 10, respectively. For human biodistribution data, the calculated effective dose was 31 ± 1 μSv/MBq, and the urinary bladder wall had the highest absorbed dose at 376 ± 19 μGy/MBq using the 4.8-h bladder-voiding model. With the 1-h voiding model, these doses reduced to 15 ± 1 μSv/MBq for the effective dose and 103 ± 4 μGy/MBq for the absorbed dose in the urinary bladder wall. For a typical injected activity of 555 MBq, the effective dose would be 17.2 ± 0.6 mSv for the 4.8-h model, reducing to 8.3 ± 0.4 mSv for the 1-h model. For monkey biodistribution data, the effective dose to humans would be 22.2 ± 2.4 mSv for the 4.8-h model and 12.8 ± 0.2 mSv for the 1-h model.
The biodistribution profile of (18)F-RGD-K5 in monkeys and humans was similar, with increased uptake in the bladder, liver, and kidneys. There was rapid clearance of (18)F-RGD-K5 through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both whole-body effective dose and bladder dose can be reduced by more frequent voiding. (18)F-RGD-K5 can be used safely for imaging α(v)β(3) integrin expression in humans.
The natural products colchicine and combretastatin A-4 (
CA4
) have provided inspiration for the discovery and development of a wide array of derivatives and analogues that inhibit tubulin ...polymerization through a binding interaction at the colchicine site on β-tubulin. A water-soluble phosphate prodrug salt of
CA4
(referred to as
CA4P
) has demonstrated the ability to selectively damage tumor-associated vasculature and ushered in a new class of developmental anticancer agents known as vascular disrupting agents (VDAs). Through a long-term program of structure activity relationship (SAR) driven inquiry, we discovered that the dihydronaphthalene molecular scaffold provided access to small-molecule inhibitors of tubulin polymerization. In particular, a dihydronaphthalene analogue bearing a pendant trimethoxy aryl ring (referred to as
KGP03
) and a similar aroyl ring (referred to as
KGP413
) were potent inhibitors of tubulin polymerization (IC
50
= 1.0 and 1.2 μM, respectively) and displayed low nM cytotoxicity against human cancer cell lines. In order to enhance water-solubility for
in vivo
evaluation, the corresponding phosphate prodrug salts (
KGP04
and
KGP152
, respectively) were synthesized. In a preliminary
in vivo
study in a SCID-BALB/c mouse model bearing the human breast tumor MDA-MB-231-luc, a 99% reduction in signal was observed with bioluminescence imaging (BLI) 4 h after IP administration of
KGP152
(200 mg kg
−1
) indicating reduced tumor blood flow. In a separate study, disruption of tumor-associated blood flow in a Fischer rat bearing an A549-luc human lung tumor was observed by color Doppler ultrasound following administration of
KGP04
(15 mg kg
−1
).
Dihydronaphthalene analogues as potent inhibitors of tubulin polymerization, cytotoxic agents, and vascular disrupting agents (VDAs).
Dihydronaphthalene analogues as potent inhibitors of tubulin polymerization, cytotoxic agents, and vascular disrupting agents (VDAs).
The natural products colchicine and combretastatin A-4 (
CA4
) ...have provided inspiration for the discovery and development of a wide array of derivatives and analogues that inhibit tubulin polymerization through a binding interaction at the colchicine site on β-tubulin. A water-soluble phosphate prodrug salt of
CA4
(referred to as
CA4P
) has demonstrated the ability to selectively damage tumor-associated vasculature and ushered in a new class of developmental anticancer agents known as vascular disrupting agents (VDAs). Through a long-term program of structure activity relationship (SAR) driven inquiry, we discovered that the dihydronaphthalene molecular scaffold provided access to small-molecule inhibitors of tubulin polymerization. In particular, a dihydronaphthalene analogue bearing a pendant trimethoxy aryl ring (referred to as
KGP03
) and a similar aroyl ring (referred to as
KGP413
) were potent inhibitors of tubulin polymerization (IC
50
= 1.0 and 1.2 μM, respectively) and displayed low nM cytotoxicity against human cancer cell lines. In order to enhance water-solubility for
in vivo
evaluation, the corresponding phosphate prodrug salts (
KGP04
and
KGP152
, respectively) were synthesized. In a preliminary
in vivo
study in a SCID-BALB/c mouse model bearing the human breast tumor MDA-MB-231-luc, a 99% reduction in signal was observed with bioluminescence imaging (BLI) 4 h after IP administration of
KGP152
(200 mg kg
–1
) indicating reduced tumor blood flow. In a separate study, disruption of tumor-associated blood flow in a Fischer rat bearing an A549-luc human lung tumor was observed by color Doppler ultrasound following administration of
KGP04
(15 mg kg
–1
).
2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4- (3-^sup 18^F-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4, 5-trihydroxytetrahydro-2H-pyran-2-carboxamido)butyl)-11-(3- ...guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan- 2-yl)acetic acid (^sup 18^F-RGD-K5) has been developed as an α^sub v^β^sub 3^ integrin marker for PET. The purpose of this study was to determine the biodistribution and estimate the radiation dose from ^sup 18^F-RGD-K5 using whole-body PET/CT scans in monkeys and humans. Methods: Successive wholebody PET/CT scans were obtained after intravenous injection of ^sup 18^F-RGD-K5 in 3 rhesus monkeys (167±19 MBq) and 4 healthy humans (583±78 MBq). In humans, blood samples were collected between the PET/CT scans, and stability of ^sup 18^F-RGDK5 was assessed. Urine was also collected between the scans, to determine the total activity excreted in urine. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on human and monkey biodistributions. Results: ^sup 18^F-RGD-K5 was metabolically stable in human blood up to 90 min after injection, and it cleared rapidly from the blood pool, with a 12-min half-time. For both monkeys and humans, increased ^sup 18^F-RGD-K5 uptake was observed in the kidneys, bladder, liver, and gallbladder, with mean standardized uptake values at 1 h after injection for humans being approximately 20, 50, 4, and 10, respectively. For human biodistribution data, the calculated effective dose was 31±1 mSv/MBq, and the urinary bladder wall had the highest absorbed dose at 376±19 mGy/MBq using the 4.8-h bladder-voiding model. With the 1-h voiding model, these doses reduced to 15±1 mSv/MBq for the effective dose and 103±4 mGy/MBq for the absorbed dose in the urinary bladder wall. For a typical injected activity of 555 MBq, the effective dose would be 17.2±0.6 mSv for the 4.8-h model, reducing to 8.3±0.4 mSv for the 1-h model. For monkey biodistribution data, the effective dose to humans would be 22.2±2.4 mSv for the 4.8-h model and 12.8±0.2 mSv for the 1-h model. Conclusion: The biodistribution profile of ^sup 18^FRGD- K5 in monkeys and humans was similar, with increased uptake in the bladder, liver, and kidneys. There was rapid clearance of ^sup 18^F-RGD-K5 through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both whole-body effective dose and bladder dose can be reduced by more frequent voiding. ^sup 18^F-RGD-K5 can be used safely for imaging α^sub v^β^sub 3^ integrin expression in humans. PUBLICATION ABSTRACT
CAII makes a good PET: Discovering positron emission tomography (PET) probes with high target affinities is challenging. PET probe discovery using insitu click chemistry uses (19) F-bearing fragments ...as (18) Fsurrogates. This ensures that the lead hits and PET probes have equivalent chemical or biological characteristics, making PET probe discovery predictable and reliable.
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